Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo.
Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo.
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DOI：
10.3390/microorganisms9030566
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发表时间：
2021-03-10
期刊：
影响因子：
4.5
通讯作者：
White JM
中科院分区：
文献类型：
--
作者：
Finch CL;Dyall J;Xu S;Nelson EA;Postnikova E;Liang JY;Zhou H;DeWald LE;Thomas CJ;Wang A;Xu X;Hughes E;Morris PJ;Mirsalis JC;Nguyen LH;Arolfo MP;Koci B;Holbrook MR;Hensley LE;Jahrling PB;Schmaljohn C;Johansen LM;Olinger GG;Schiffer JT;White JM
埃博拉病毒(Ebola ebolaVirus，EBOV)的暴发具有高发病率和高死亡率。最近在EBOV病(EVD)的管理方面取得了里程碑式的进展，获得了EBOV疫苗和两种单抗疗法的许可。然而，对于其他致病的丝状病毒，既没有疫苗也没有治疗方法。为了应对此类暴发，以及更便捷、更具成本效益的埃博拉病毒管理，我们寻求一种含有口服可用和室温稳定的药物的鸡尾酒，该药物对多种丝状病毒具有很强的活性。我们以前发现(贝普地尔+舍曲林)和(舍曲林+托瑞米芬)在细胞培养中协同抑制EBOV。在这里，我们描述了在EVD小鼠模型中测试这些组合的步骤。我们确定了一种适合口服给药的载体，并确定了这样配制的药物对EBOV的活性与在DMSO中的制剂相同，并且它们在溶液中储存长达7天时保持活性。药代动力学(PK)研究表明，口服给药载体中的药物在受试最高剂量的小鼠体内耐受性良好。总的来说，这些数据支持这些组合在EVD小鼠模型中的协同测试中的进步。此外，基于人类口服PK的数学模型预测，这些组合在人类身上将比其组成的单一药物更活跃。
Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here, we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.
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影响因子：
64.8
作者：
Cote, Marceline;Misasi, John;Ren, Tao;Bruchez, Anna;Lee, Kyungae;Filone, Claire Marie;Hensley, Lisa;Li, Qi;Ory, Daniel;Chandran, Kartik;Cunningham, James
通讯作者：
Cunningham, James
影响因子：
3.7
作者：
Feneant, Lucie;Szymanska-de Wijs, Katarzyna M.;White, Judith M.
通讯作者：
White, Judith M.
影响因子：
4
作者：
Cheng, Yu-Shan;Williamson, Peter R.;Zheng, Wei
通讯作者：
Zheng, Wei
影响因子：
158.5
作者：
Gulick, RM;Mellors, JW;Chodakewitz, JA
通讯作者：
Chodakewitz, JA
DOI：
10.3390/v8110277
发表时间：
2016-10-27
期刊：
Viruses
影响因子：
--
作者：
Dowall SD;Bewley K;Watson RJ;Vasan SS;Ghosh C;Konai MM;Gausdal G;Lorens JB;Long J;Barclay W;Garcia-Dorival I;Hiscox J;Bosworth A;Taylor I;Easterbrook L;Pitman J;Summers S;Chan-Pensley J;Funnell S;Vipond J;Charlton S;Haldar J;Hewson R;Carroll MW
通讯作者：
Carroll MW