Pathogenetic treatment of influenza patients with aerosolized form of aprotinin, a protease inhibitor

Therapeutic and antiviral efficacies of inhalations of aerosolized aprotinin, a protease inhibitor, which blocks a stage of influenza virus proteolytic activation, were studied. This clinical study was performed during winter-spring outbreak caused with pandemic Influenza H1N1pdm09. Aprotinin (a natural low molecular weight antiprotease polypeptide) is known to be a chemotherapeutic antiviral drug, which inhibits influenza virus proteolytic activation accomplished by host respiratory proteases. Patients inhaled 2 aerosol doses of aprotinin (160 Kallikrein-inhibiting Units (KIU)) each 2 hours for 5 days. In comparison group, patients were treated with ingavirin (a synthetic peptidoamine with unknown antiviral target), 90 mg per day for 5 days. About 10-fold decrease of virus load in aprotinin patients were determined in comparison to ingavirin patients. Duration of clinical symptoms, such as rhinorrhea, weakness, headache, sore throat, cough, sore thorax, fever, was 1 -2 days shorter in aprotinin then in ingavirin group. Side effects and patient discomfort were not revealed in aprotinin group patients. Aerosolized form of aprotinin can be recommended as a pathogenetic antiviral drug against Influenza caused by different viruses, including seasonal H1N1, H2N2, H3N2, swine-like H1N1pdm09, and avian-like H7N9 viruses.

influenza, pathogenesis, aprotinin, chemotherapeutic compound, therapy, proteolytic activation, грипп, патогенез, апротинин, химиопрепарат, лечение, протеолитическая активация

1. Das K. Antivirals targeting influenza A virus. J Med Chem. 2012; 55: 6263-77.

2. Lee S.M., Yen H.L. Targeting the host or the virus: current and novel concepts for antiviral approaches against influenza virus infection. Antiviral Res. 2012; 96(3): 391-404.

3. Жирнов О.П. Протеолитическая активация миксовирусов и новая стратегия в лечении вирусных заболеваний. Вопросы вирусологии 1983; (4): 9-21.

4. Жирнов О.П., Малышев Н.А. Апротинин., ингибитор протеаз., - новая альтернатива в лечении гриппа. Русский медицинский журнал 2012; (2): 52-6.

5. Zhirnov O.P., Klenk H.D., Wright P.F. Aprotinin and similar protease inhibitors as drugs against influenza. Antiviral Res. 2011; 92(1): 27-36.

6. Жирнов О.П., Поярков С.В., Малышев Н.А. Мишени противовирусного и противовоспалительного действия апротинина: перспективы нового использования. Пульмонология 2009; 33(3): 27-33.

7. Zhirnov O.P., Ikizler M.R., Wright P. Cleavage of influenza A virus hemagglutinin in human respiratory epithelium is cell-associated and sensitive to exogenous antiproteases. J Virol. 2002; 76: 8682-9.

8. Zhirnov O.P., Matrosovich T.Y., Matrosovich M.N., Klenk H.D. Aprotinin., a protease inhibitor., suppresses proteolytic activation of pandemic H1N1v influenza virus. Antiviral Chem Chemother. 2011; 21: 169-74.

9. Kido H., Okumura Y., Takahashi E., et al. Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure. Biochim Biophys Acta. 2012; 1824(1): 186-94.

10. Böttcher-Friebertshäuser E., Lu Y., Meyer D., et al. Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections. Vaccine 2012; 30(51): 7374-80.

11. Bertram S., Glowacka I., Steffen I., et al. Novel insights into proteolytic cleavage of influenza virus hemagglutinin. Rev Med Virol. 2010; 20(5): 298-310.

12. Жирнов О.П., Киржнер Л.С., Овчаренко А.В., Малышев Н.А. Патогенетическая терапия острых респираторных заболеваний ингаляциями апротинина. Терапевтический архив 1995; (6): 38-42.

13. Жирнов О.П., Киржнер Л.С., Овчаренко А.В., Малышев Н.А. Клиническая эффективность аэрозоля апротинина при гриппе и парагриппе. Вестник РАМН 1996; (5): 26-31.

14. Zhirnov O.P., Kirzhner L.S., Ovcharenko A.V., Malyshev NA. Aerosolized aprotinin is an effective drug against viral respiratory illness. Antiinfective Drug and Chemother. 1996; 14:209-16.

15. Жирнов О.П., Сафонова Е.А., Овчаренко А.В., Малышев Н.А. Терапевтическая эффективность ингаляций апротинина у больных с острой респираторной вирусной инфекцией. Терапевтический архив 2015 (в печати).

16. Ovcharenko A.V., Zhirnov O.P. Aprotinin aerosol treatment of influenza and paramyxovirus bronchopneumonia of mice. Antiviral Res. 1994; 23: 107- 18.

17. Колобухина Л.В., Малышев Н.А., Меркулова Л.Н. и др. Изучение эффективности и безопасности нового противовирусного препарата Ингавирин при лечении больных гриппом. Русский медицинский журнал 2008; 16(22): 1502-06.

18. Колобухина Л.В., Меркулова Л.Н., Щелканов М.Ю. и др. Эффективность ингавирина в лечении гриппа у взрослых. Терапевтический архив 2009; 81(3): 51-4.

19. Зарубаев В.В., Слита А.В., Белявская С.В. и др. Противовирусная активность Ингавирина на модели экспериментальной диссеминированной аденовирусной инфекции у животных. Вопросы вирусологии 2011; (6): 23-7.

20. Зарубаев В.В., Гаршинина А.В., Калинина Н.А. и др. Влияние ингавирина на ультраструктурные особенности морфогенеза парагриппозной инфекции in vitro и in vivo. Вопросы вирусологии 2012; (5): 32-8.

21. Planés C., Caughey G.H. Regulation of the epithelial Na+ channel by peptidases. Curr Top Dev Biol. 2007; 78: 23-46.

22. Coote K., Atherton-Watson H.C., Sugar R., et al. Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease. J Pharmacol Exp Ther. 2009; 329(2): 764-74.

23. Nimishakavi S., Besprozvannaya M., Raymond W.W., et. al. Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces of human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 2012; 303(2): L97-106.

24. Li Q., Zhou L., Zhou M., Chen Z., Li F., et al. Preliminary Report: Epidemiology of the Avian Influenza A (H7N9) Outbreak in China. N Engl J Med. 2013; Apr 24. PubMed PMID: 23614499.

25. Kageyama T., Fujisaki S., Takashita E., et. al. Genetic analysis of novel avian A(H7N9) influenza viruses isolated from patients in China, February to April 2013. Euro Surveill. 2013; 18(15): 20453 [PubMed].

26. Lu S.H., Xi X.H., Zheng Y.F., et al. Analysis of the clinical characteristics and treatment of two patients with avian influenza virus (H7N9). Biosci Trends 2013; 7(2): 109-12.

27. Beaulieu A., Gravel É., Cloutier A., et. al. Matriptase proteolytically activates influenza virus and promotes multicycle replication in the human airway epithelium. J Virol. 2013; 87(8): 4237-51.

28. Bertram S., Glowacka I., Blazejewska P., et al. TMPRSS2 and MPRSS4 facilitate trypsin-independent spread of influenza virus in Caco-2 cells. J Virol. 2010; 84(19): 10016-25.

29. Böttcher E., Matrosovich T., Beyerle M., et al. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol. 2006; 80(19): 9896-8.

30. Böttcher-Friebertshäuser E., Freuer C., Sielaff F., et al. Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol. 2010; 84(11): 5605-14.

31. Chaipan C., Kobasa D., Bertram S., et al. Proteolytic activation of the 1918 influenza virus hemagglutinin. J Virol. 2009; 83(7): 3200-11.