Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Antimicrob Agents Chemother. 2012 Dec;56(12):6328-33. doi: 10.1128/AAC.01664-12. Epub 2012 Oct 1.
Compounds lacking oral activity may be delivered intranasally to treat influenza virus infections in mice. However, intranasal treatments greatly enhance the virulence of such virus infections. This can be partially compensated for by giving reduced virus challenge doses. These can be 100- to 1,000-fold lower than infections without such treatment and still cause equivalent mortality. We found that intranasal liquid treatments facilitate virus production (probably through enhanced virus spread) and that lung pneumonia was delayed by only 2 days relative to a 1,000-fold higher virus challenge dose not accompanied by intranasal treatments. In one study, zanamivir was 90 to 100% effective at 10 mg/kg/day by oral, intraperitoneal, and intramuscular routes against influenza A/California/04/2009 (H1N1) virus in mice. However, the same compound administered intranasally at 20 mg/kg/day for 5 days gave no protection from death although the time to death was significantly delayed. A related compound, Neu5Ac2en (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid), was ineffective at 100 mg/kg/day. Intranasal zanamivir and Neu5Ac2en were 70 to 100% protective against influenza A/NWS/33 (H1N1) virus infections at 0.1 to 10 and 30 to 100 mg/kg/day, respectively. Somewhat more difficult to treat was A/Victoria/3/75 virus that required 10 mg/kg/day of zanamivir to achieve full protection. These results illustrate that treatment of influenza virus infections by the intranasal route requires consideration of both virus challenge dose and virus strain in order to avoid compromising the effectiveness of a potentially useful antiviral agent. In addition, the intranasal treatments were shown to facilitate virus replication and promote lung pathology.
缺乏口服活性的化合物可以经鼻腔给药来治疗小鼠的流感病毒感染。然而，鼻腔治疗会极大地增强此类病毒感染的毒力。这可以通过给予降低的病毒攻击剂量来部分补偿。这些剂量可以比没有这种治疗的感染低 100 到 1000 倍，但仍会导致同等的死亡率。我们发现，鼻腔液体治疗促进了病毒的产生（可能是通过增强病毒传播），并且与不进行鼻腔治疗但伴随有 1000 倍更高的病毒攻击剂量的感染相比，肺部肺炎仅延迟了 2 天。在一项研究中，扎那米韦以 10mg/kg/天的剂量经口服、腹腔内和肌肉内途径对小鼠中的流感 A/加利福尼亚/04/2009（H1N1）病毒的有效率为 90%至 100%。然而，相同的化合物以 20mg/kg/天的剂量经鼻腔给药 5 天没有提供对死亡的保护，尽管死亡时间明显延迟。一种相关的化合物 Neu5Ac2en（N-乙酰-2,3-脱氢-2-脱氧神经氨酸）以 100mg/kg/天的剂量无效。鼻腔内扎那米韦和 Neu5Ac2en 以 0.1 至 10 和 30 至 100mg/kg/天的剂量分别对流感 A/NWS/33（H1N1）病毒感染有 70%至 100%的保护作用。更难治疗的是 A/Victoria/3/75 病毒，需要 10mg/kg/天的扎那米韦才能实现完全保护。这些结果表明，通过鼻腔途径治疗流感病毒感染需要考虑病毒攻击剂量和病毒株，以避免损害潜在有用的抗病毒药物的有效性。此外，鼻腔治疗被证明促进了病毒复制并促进了肺部病理学。
