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流感病毒对奥司他韦的敏感性和耐药性。

Influenza virus susceptibility and resistance to oseltamivir.

作者信息

Aoki Fred Y, Boivin Guy, Roberts Noel

机构信息

Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, Canada.

出版信息

Antivir Ther. 2007;12(4 Pt B):603-16.

Abstract

Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a highly specific inhibitor of influenza virus neuraminidases. Given that oseltamivir carboxylate binds to highly conserved, essential amino acids in the catalytic site of the enzyme, and that the activity of neuraminidase is critical for virus release from infected cells and subsequent virus spread, the drug was expected to have a low propensity to select for viable resistant mutants. Indeed, viruses with neuraminidase (and haemagglutinin) substitutions conferring reduced susceptibility to oseltamivir have been generated with difficulty in vitro, and these mutants generally have reduced infectivity and transmissibility compared with wild-type virus in animal models. Studies of seasonal influenza isolates collected before the introduction of oseltamivir show an absence of naturally occurring resistance. Few resistant mutants have arisen during clinical trials of oseltamivir in seasonal influenza, with cumulative data from all Roche-sponsored studies indicating an incidence of resistance of 0.32% in adults (0.4%, including low-level mutants detected by genotyping alone in mixed virus populations) and 4.1% (5.4%) in children. Higher incidences of resistance were observed in two small Japanese studies, in which children received a different dosing schedule from their Western counterparts. In summary, the overall incidence of influenza virus resistance associated with the seasonal use of oseltamivir is currently low and resistant viruses might be of little clinical significance, except perhaps in immunocompromised individuals. However, continued vigilance, especially of emerging avian H5N1 strains, combined with careful, systematic laboratory-based monitoring, is essential.

摘要

磷酸奥司他韦是奥司他韦羧酸盐的前体药物,奥司他韦羧酸盐是一种高度特异性的流感病毒神经氨酸酶抑制剂。鉴于奥司他韦羧酸盐与该酶催化位点中高度保守的必需氨基酸结合,且神经氨酸酶的活性对于病毒从受感染细胞中释放以及随后的病毒传播至关重要,预计该药物选择产生存活耐药突变体的倾向较低。实际上,在体外很难产生具有对奥司他韦敏感性降低的神经氨酸酶(和血凝素)替代的病毒,并且在动物模型中,与野生型病毒相比,这些突变体的感染性和传播性通常较低。对在引入奥司他韦之前收集的季节性流感分离株的研究表明不存在天然耐药性。在奥司他韦治疗季节性流感的临床试验期间,很少出现耐药突变体,罗氏公司所有研究的累积数据表明,成人耐药发生率为0.32%(包括仅通过基因分型在混合病毒群体中检测到的低水平突变体时为0.4%),儿童为4.1%(5.4%)。在两项小型日本研究中观察到更高的耐药发生率,其中儿童接受的给药方案与西方儿童不同。总之,与季节性使用奥司他韦相关的流感病毒耐药总体发生率目前较低,耐药病毒可能临床意义不大,免疫功能低下个体可能除外。然而,持续保持警惕,特别是对新出现的禽H5N1毒株,同时结合基于实验室的仔细、系统监测,至关重要。

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