Histology results for Rhesus Macaques (RM).

Ebola virus (EBOV) causes a severe and often fatal hemorrhagic fever in humans for which effective postexposure countermeasures are lacking. Herein, we describe the evaluation of an S-adenosylhomocysteine hydrolase inhibitor, MSD-914, using mouse and nonhuman primate (NHP) models of lethal EBOV. Mice were completely protected from severe disease and death at doses as low as 0.31 mg/kg/day administered orally. From the pharmacological data and a toxicokinetic study, a predicted protective dose was selected for rhesus macaques (RMs). Surprisingly, orally administered MSD-914 was unable to protect RMs at doses as high as 0.8 mg/kg/day despite providing similar exposure of the drug to the efficacious dose observed in the mouse model.埃博拉病毒（Ebola virus, EBOV）可引发人类罹患严重且常致死的出血热，目前尚无有效的暴露后防治手段。本文描述了针对S-腺苷同型半胱氨酸水解酶抑制剂MSD-914的评估研究，该研究采用致死性埃博拉病毒感染的小鼠与非人灵长类（nonhuman primate, NHP）模型。当口服给药剂量低至0.31 mg/kg/日时，小鼠可完全免受重症疾病与死亡威胁。基于药理学数据与毒代动力学研究，我们为恒河猴（rhesus macaques, RMs）选定了预测保护性剂量。令人意外的是，尽管该给药方案在小鼠模型中达到了有效剂量对应的药物暴露水平，但口服给药剂量高达0.8 mg/kg/日时，MSD-914仍无法对恒河猴起到保护作用。