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Abstract：
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.
摘要：
埃博拉病毒（EBOV）的爆发与高发病率和死亡率有关。最近在EBOV疾病（EVD）的管理方面已经达到了里程碑，并获得了EBOV疫苗和两种单克隆抗体疗法的许可。然而,对于其他致病丝状病毒，既没有疫苗也没有治疗方法。为了准备这种爆发，为了更容易和更具成本效益地管理EVD，我们寻求一种含有口服和室温稳定的药物的鸡尾酒，对多种丝状病毒具有很强的活性。我们先前表明（贝普地尔舍曲林）和（舍曲林托瑞米芬）协同抑制细胞培养物中的EBOV。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，如此配制的药物与DMSO中的制剂一样具有相同的抗EBOV活性，它们在溶液中储存后保持活性长达七天。药代动力学(PK)研究表明,口服递送载体中的药物在测试的最高剂量下在小鼠中是良好耐受的。数据总体上支持这些组合在EVD小鼠模型中测试协同作用的进展。此外，基于人类口服PK的数学模型预测，这些组合在人类中的活性比其成分单一药物更高。
