Treatment of late stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin.
Treatment of late stage disease in a model of arenaviral hemorrhagic fever: T-705 efficacy and reduced toxicity suggests an alternative to ribavirin.
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DOI：
10.1371/journal.pone.0003725
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Morrey JD
中科院分区：
文献类型：
--
作者：
Gowen BB;Smee DF;Wong MH;Hall JO;Jung KH;Bailey KW;Stevens JR;Furuta Y;Morrey JD
已知越来越多的沙粒病毒会引起病毒性出血热 (HF)，这是一种严重且危及生命的综合征，其特征为发烧、不适和血管通透性增加。利巴韦林是唯一获得许可用于治疗某些沙病毒性心力衰竭的抗病毒药物，其成功与否有好有坏，但毒性也很大。由于严重的沙粒病毒感染最初并不表现出明显的症状，并且很难在早期阶段进行临床诊断，因此确定在感染后期有效的抗病毒疗法至关重要。我们之前曾报道过，T-705 是一种取代的吡嗪衍生物，目前正在开发作为抗流感药物，在感染皮钦德病毒的仓鼠感染过程中早期口服该药物时，该药物对感染皮钦德病毒的仓鼠具有高度活性。在这里，我们证明，当仓鼠生病后和动物开始死于疾病的前一天开始治疗时，T-705 可以对仓鼠的这种致命的沙粒病毒感染提供显着的保护。重要的是，这与大多数器官中病毒载量达到峰值并且明显组织损伤的时间一致。我们还表明，T-705 与利巴韦林一样有效，但毒性较小，因为与利巴韦林治疗的动物相比，接受 T-705 治疗的受感染仓鼠平均能更好地保持体重并恢复得更快。此外，T-705 和利巴韦林联合治疗没有额外的益处。最后，药代动力学数据表明，口服给药后血浆 T-705 水平在疾病后期显着降低，并且可能导致在感染第 7 天停止治疗时出现的疗效降低。我们的研究结果支持 T-705 用于治疗严重沙病毒感染的进一步临床前开发。
A growing number of arenaviruses are known to cause viral hemorrhagic fever (HF), a severe and life-threatening syndrome characterized by fever, malaise, and increased vascular permeability. Ribavirin, the only licensed antiviral indicated for the treatment of certain arenaviral HFs, has had mixed success and significant toxicity. Since severe arenaviral infections initially do not present with distinguishing symptoms and are difficult to clinically diagnose at early stages, it is of utmost importance to identify antiviral therapies effective at later stages of infection. We have previously reported that T-705, a substituted pyrazine derivative currently under development as an anti-influenza drug, is highly active in hamsters infected with Pichinde virus when the drug is administered orally early during the course of infection. Here we demonstrate that T-705 offers significant protection against this lethal arenaviral infection in hamsters when treatment is begun after the animals are ill and the day before the animals begin to succumb to disease. Importantly, this coincides with the time when peak viral loads are present in most organs and considerable tissue damage is evident. We also show that T-705 is as effective as, and less toxic than, ribavirin, as infected T-705-treated hamsters on average maintain their weight better and recover more rapidly than animals treated with ribavirin. Further, there was no added benefit to combination therapy with T-705 and ribavirin. Finally, pharmacokinetic data indicate that plasma T-705 levels following oral administration are markedly reduced during the latter stages of disease, and may contribute to the reduced efficacy seen when treatment is withheld until day 7 of infection. Our findings support further pre-clinical development of T-705 for the treatment of severe arenaviral infections.
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影响因子：
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作者：
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通讯作者：
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