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- W1978586142 abstract "BMS-708163, in Phase II development for Alzheimer's Disease, selectively inhibits Aβ synthesis relative to Notch, and is a potent and orally active γ-secretase inhibitor. Objective: To characterize the immunologic profile of BMS-708163 in rats. This investigation was initiated in response to decreases in peripheral blood (PB) and splenic lymphocytes observed in rats administered BMS-708163 (AUC ≥32900 ng•h/mL, ∼4X clinically active exposure) daily for 1 month. To characterize the effects of BMS-708163 on PB and splenic lymphocytes and explore the relationship between affected immune parameters and net immune health, BMS-708163 was administered to rats for 4-6 weeks in a series of studies, including 2 host-resistance models conducted in aged rats to reflect the age of the patient population (1: a streptococcal model where rats were challenged IV with Streptococcus pneumoniae, a blood-borne pathogen infection that reportedly requires splenic marginal zone (MZ) activity for clearance, and 2: an intranasal influenza A model where complex interactions of cell-mediated and humoral immune functions are required for viral clearance). Criteria for evaluation included survival; pathogen clearance; flow-cytometric-based PB and splenic T-cell, B-cell, and IgM phenotyping; immunofluorescence analyses of splenic T-cell, B-cell, and IgM; and antibody response. Exposure-dependent decreases in IgM expression per circulating B-cell were observed at AUC ≥3000 ng•h/mL. At AUC ≥ 4670 ng•h/mL, a decreased number of IgM+ B-cells in the splenic MZ was observed. At higher exposures (≥22800 ng•h/mL), decreases in PB T- and B-cells, and splenic T-cells were associated with marked suppression of T-cell-dependent antibody response to keyhole limpet hemocyanin. In both host-resistance models, similar PB and splenic lymphoid changes occurred and IgM-specific antibody responses to streptococcus and influenza were impaired; however, there were no drug-related effects on survival or overall pathogen clearance supporting that the complexity and redundancy of the immune system provided sufficient net immunocompetence in the presence of γ-secretase inhibition. In 2 host-resistance models in aged rats, decreases in PB and splenic lymphocytes associated with BMS-708163 administration did not adversely affect net immune health. This is consistent with the results of previous 3- and 6-month rat toxicology studies, where no opportunistic infections occurred." @default.
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- W1978586142 date "2010-07-01" @default.
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- W1978586142 title "P3-293: A comprehensive immunotoxicologic investigation of a gamma secretase inhibitor in rats" @default.
- W1978586142 doi "https://doi.org/10.1016/j.jalz.2010.05.1793" @default.
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