Calfee D P, Hayden F G
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, USA.
Drugs. 1998 Oct;56(4):537-53. doi: 10.2165/00003495-199856040-00003.
Epidemic influenza continues to be associated with significant morbidity in the general population, and mortality in the elderly and other high risk patients. Although the case fatality rate averages less than 0.01%, tens of thousands of deaths occur each year. Control through immunisation programmes has not been possible due to incomplete protective efficacy and antigenic variations that occur frequently. Currently available anti-influenza medications (amantadine and rimantadine) have had limited success due to underutilisation, lack of activity against influenza B, the rapid development of viral resistance to the drugs, and adverse effects. A new class of antiviral agents designed to inhibit influenza neuraminidase, an important surface glycoprotein, is currently under active development for use in the prophylaxis and treatment of influenza A and B infections. Two of these compounds, zanamivir (GG167) and GS4104 (the ethyl ester prodrug of GS4071) have reached clinical trials. Most studies of zanamivir have involved topical administration by inhalation of dry powder aerosols and/or intranasal doses of aqueous solutions. These routes rapidly provide high local concentrations at the sites of delivery. GS4104 is administered orally, which allows for greater ease of administration, and probably more uniform distribution of the parent compound GS4071 in the respiratory tract. Both have shown potent inhibitory activity against influenza in animal models and experimental human influenza with excellent tolerability profiles. Zanamivir treatment has been shown to reduce the severity and duration of naturally occurring, uncomplicated influenza illness in adults. Clinical resistance to these drugs has not been recognised as a significant problem to date, although strains resistant to each agent have been produced in the laboratory. This class of agents shows considerable promise as a novel approach to prophylaxis and treatment of influenza infections. Ongoing studies should provide the data needed to allow the addition of 1 or more of the neuraminidase inhibitors to the clinician's anti-influenza armamentarium.
流行性感冒在普通人群中仍然会引发严重疾病，并导致老年人及其他高危患者死亡。虽然病死率平均低于0.01%，但每年仍有上万人死亡。由于保护效果不完全以及抗原频繁变异，通过免疫计划进行控制已无法实现。目前可用的抗流感药物（金刚烷胺和金刚乙胺）由于使用不足、对B型流感无活性、病毒对药物的快速耐药性发展以及不良反应，取得的成功有限。一类旨在抑制流感神经氨酸酶（一种重要的表面糖蛋白）的新型抗病毒药物目前正在积极研发中，用于预防和治疗甲型和乙型流感感染。其中两种化合物，扎那米韦（GG167）和GS4104（GS4071的乙酯前体药物）已进入临床试验阶段。扎那米韦的大多数研究涉及通过吸入干粉气雾剂和/或鼻内给予水溶液进行局部给药。这些给药途径能在给药部位迅速提供高局部浓度。GS4104通过口服给药，这使得给药更加方便，并且母体化合物GS4071在呼吸道中的分布可能更均匀。两者在动物模型和实验性人类流感中均显示出对流感的强效抑制活性，且耐受性良好。扎那米韦治疗已被证明可减轻成人自然发生的、无并发症流感疾病的严重程度并缩短病程。尽管在实验室中已产生对每种药物耐药的毒株，但迄今为止，临床耐药性尚未被视为一个重大问题。这类药物作为预防和治疗流感感染的新方法显示出巨大潜力。正在进行的研究应能提供所需数据，以便在临床医生的抗流感药物库中增加一种或多种神经氨酸酶抑制剂。
