Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic Fever.
Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic Fever.
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DOI：
10.1371/journal.pntd.0001342
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发表时间：
2011-10
影响因子：
3.8
通讯作者：
Gowen BB
中科院分区：
文献类型：
--
作者：
Mendenhall M;Russell A;Smee DF;Hall JO;Skirpstunas R;Furuta Y;Gowen BB
拉沙病毒和Junín病毒是沙病毒科病毒中最突出的成员，分别引起病毒性出血热综合征拉沙热和阿根廷出血热。目前，利巴韦林是唯一用于治疗这些疾病的抗病毒药物，但由于其对晚期病例的疗效有限及其毒性，需要更安全，更有效的抗病毒药物。在这里，我们使用了一种基于pichind<s:1>病毒（PICV）适应株攻击的近交豚鼠急性沙粒病毒感染模型，以进一步临床前开发T-705 (Favipiravir)，这是一种有前途的RNA病毒感染广谱抑制剂。豚鼠适应的19代PICV具有均匀致死性，LD50为~ 5个斑块形成单位，疾病与发热、体重减轻、血小板减少、凝血缺陷、血清天冬氨酸转氨酶（AST）浓度升高和嗜性病毒感染相关。Favipiravir （300 mg/kg/天，每日两次口服，持续14天）非常有效，因为所有动物都从picv诱导的疾病中完全恢复，即使在病毒攻击后一周，当动物已经出现明显的发热和血小板减少症时开始治疗。抗病毒活性和疾病严重程度的降低是由favipirvir治疗动物的峰值血清病毒滴度和AST浓度的显著降低所证明的。此外，在治疗开始后不久，观察到体温急剧下降。口服利巴韦林也进行了评估，虽然有效，但恢复速度较慢可能是该药物已知毒性的标志。我们的研究结果支持进一步开发favipiravir来治疗严重的沙粒病毒感染。在PICV豚鼠模型中优化实验性favipiravir治疗方案将为基于高致病性沙病毒（如Lassa和Junín）攻击的同一物种的关键未来研究提供信息。沙粒病毒科的几种病毒引起严重危及生命的出血热综合征，在非洲和南美洲的流行地区被认为是被忽视的热带病。利巴韦林是唯一许可使用的抗病毒药物，在治疗晚期病例时疗效有限，并且与毒性有关。在本研究中，我们利用豚鼠急性沙粒病毒性疾病模型，基于pichind<s:1>沙粒病毒（PICV）的适应株感染，进一步临床前开发一种有前途的广谱抗病毒药物候选药物favipiravir。口服favipiravir对有明显发热的患病动物非常有效，因为即使在病毒攻击后一周开始治疗，所有动物都从致命的PICV感染中完全恢复。血清病毒载量和血清天冬氨酸转氨酶（一种组织损伤后释放到血液中的酶，是严重沙状病毒感染的标志）的显著降低证明了抗病毒活性和疾病严重程度的降低。此外，在治疗开始后不久，观察到发烧急剧下降。我们的研究结果支持进一步开发favipiravir用于治疗严重沙状病毒感染，目前尚无安全有效的治疗晚期沙状病毒感染的方法。
Lassa and Junín viruses are the most prominent members of the Arenaviridae family of viruses that cause viral hemorrhagic fever syndromes Lassa fever and Argentine hemorrhagic fever, respectively. At present, ribavirin is the only antiviral drug indicated for use in treatment of these diseases, but because of its limited efficacy in advanced cases of disease and its toxicity, safer and more effective antivirals are needed. Here, we used a model of acute arenaviral infection in outbred guinea pigs based on challenge with an adapted strain of Pichindé virus (PICV) to further preclinical development of T-705 (Favipiravir), a promising broad-spectrum inhibitor of RNA virus infections. The guinea pig-adapted passage 19 PICV was uniformly lethal with an LD50 of ∼5 plaque-forming units and disease was associated with fever, weight loss, thrombocytopenia, coagulation defects, increases in serum aspartate aminotransferase (AST) concentrations, and pantropic viral infection. Favipiravir (300 mg/kg/day, twice daily orally for 14 days) was highly effective, as all animals recovered fully from PICV-induced disease even when therapy was initiated one week after virus challenge when animals were already significantly ill with marked fevers and thrombocytopenia. Antiviral activity and reduced disease severity was evidenced by dramatic reductions in peak serum virus titers and AST concentrations in favipiravir-treated animals. Moreover, a sharp decrease in body temperature was observed shortly after the start of treatment. Oral ribavirin was also evaluated, and although effective, the slower rate of recovery may be a sign of the drug's known toxicity. Our findings support further development of favipiravir for the treatment of severe arenaviral infections. The optimization of the experimental favipiravir treatment regimen in the PICV guinea pig model will inform critical future studies in the same species based on challenge with highly pathogenic arenaviruses such as Lassa and Junín. Several viruses in the Arenaviridae family cause severe life-threatening hemorrhagic fever syndromes, which are considered neglected tropical diseases in endemic areas of Africa and South America. Ribavirin, the only licensed antiviral indicated for use has limited efficacy when treating advanced cases of disease and is associated with toxicity. In the present study, we use a model of acute arenaviral disease in guinea pigs based on infection with an adapted strain of the Pichindé arenavirus (PICV) to further preclinical development of a promising broad-spectrum antiviral drug candidate, favipiravir. Oral favipiravir was highly effective in the treatment of sick animals with marked fevers, as all recovered fully from lethal PICV infection even when therapy was initiated one week after virus challenge. Antiviral activity and reduced disease severity was evidenced by dramatic reductions in serum virus loads and serum aspartate aminotransferase, an enzyme released into the bloodstream following tissue damage and a marker for severe arenaviral infections. Moreover, a sharp decrease in fever was observed shortly after the onset of treatment. Our findings support further development of favipiravir for the treatment of severe arenaviral infections, for which there are presently no safe and effective therapies for treating advanced cases of disease.
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影响因子：
3.7
作者：
Gowen BB;Smee DF;Wong MH;Hall JO;Jung KH;Bailey KW;Stevens JR;Furuta Y;Morrey JD
通讯作者：
Morrey JD
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6.7
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作者：
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通讯作者：
de Lamballerie, X
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通讯作者：
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