Клинические аспекты применения эрдостеина при респираторных заболеваниях

Эрдостеин – препарат, созданный на основе тиола и применяемый в начале только как муколитик. Основным показанием для его применения является лечение острых и хронических заболеваний легких, сопровождающихся затрудненным отхождением мокроты. Лечебный эффект эрдостеина обусловлен действием тиоловых метаболитов, которые, кроме мукоактивных, обладают антиоксидантной, противовоспалительной и антибактериальной активностью. Экспериментальные исследования показали, что данный препарат уменьшает степень повреждения легочной ткани, вызванного окислительным стрессом, прежде всего за счет снижения продукции активных форм кислорода. Он увеличивает концентрацию IgA в слизистой оболочке дыхательных путей, уменьшая тем самым повреждающее действие табачного дыма на эндотелиальные и макрофагальные клетки. В клиническом исследовании RESTORE, изучавшем влияние эрдостеина на частоту обострений хронической обструктивной болезни легких, было продемонстрировано, что он значительно снижает риск, частоту и тяжесть обострений ХОБЛ вне зависимости от приема пациентами ингаляционных глюкокортикостероидов и уровня эозинофилов. Недавно проведенные экспериментальные работы показали, что эрдостеин также обладает способностью замедлять скорость прогрессирования фиброза в легочной ткани. Авторы исследования предположили, что этот эффект может быть связан с подавлением метаболитом эрдостеина миграции нейтрофилов, ингибированием перекисного окисления липидов и в целом регуляцией антиоксидантных механизмов защиты. Данные, полученные в последних исследованиях, также открывают новые возможности применения эрдостеина у пациентов с бронхиальной астмой и идиопатическим легочным фиброзом, значительно расширяя показания для его назначения.

1. Dechant K.L., Noble S. Erdosteine. Drugs. 1996;52(6):875–82. https://doi.org/10.2165/00003495-199652060-00009.

2. Moretti M. Pharmacology and clinical efficacy of erdosteine in chronic obstructive pulmonary disease. Expert Rev Respir Med. 2007;1(3):307–316. https://doi.org/10.1586/17476348.1.3.307.

3. Miyake K., Kaise T., Hosoe H., Akuta K., Manabe H., Ohmori K. The effect of erdosteine and its active metabolite on reactive oxygen species production by inflammatory cells. Inflamm Res. 1999;48(4):205–209. https://doi.org/10.1007/s000110050447.

4. Cazzola M., Calzetta L., Page C., Rogliani P., Matera M.G. Impact of erdosteine on chronic bronchitis and COPD: a meta-analysis. Pulm Pharmacol Ther. 2018;(48):185–194. https://doi.org/10.1016/j.pupt.2017.11.009.

5. Fioretti M., Bandera M. Prevention of exacerbations in chronic bronchitic patients with erdosteine. Med Praxis. 1991;(12):219–227.

6. Hotzinger H. Erdosteine or placebo combined with co-trimoxazole in the treatment of hypersecretive infectious bronchitis: a double blind clinical trial. Med Praxis. 1991;(12):171–181.

7. Zanasi A., Menarini A. Erdosteine versus N-acetylcysteine in the treatment of exacerbation of chronic bronchopneumopathies. Med Praxis. 1991;(12):207–217.

8. Ghiringhelli G. Cross-over study of efficacy and tolerability of erdosteine in the treatment of chronic obstructive bronchial disease in stable hypersecretive phase: controlled double-blind study vs placebo. Arch Med Int. 1995;47(4):113–120.

9. Чикина С.Ю. Муколитики: современная роль в ведении больных хронической обструктивной болезнью легких. Практическая пульмонология. 2015;(4):18–25. Режим доступа: http://www.atmosphere-ph.ru/modules/Magazines/articles/pulmo/PP_4_2015_23.pdf

10. Dal Negro R.W., Visconti M., Turco P. Efficacy of erdosteine 900 versus 600 mg/day in reducing oxi-dative stress in patients with COPD exacerbations: results of a double blind, placebocontrolled trial. Pulm Pharmacol Ther. 2015;(33):47–51. https://doi.org/10.1016/j.pupt.2015.06.004.

11. Moretti M., Bottrighi P., Dallari R., Da Porto R., Dolcetti A., Grandi P. et al. The effect of long-term treatment with erdosteine on chronic obstructive pulmonary disease: the EQUALIFE Study. Drugs Exp Clin Res. 2004;30(4):143–152. Available at: https://pubmed.ncbi.nlm.nih.gov/15553660.

12. Moretti M., Fagnani S. Erdosteine reduces inflammation and time to first exacerbation postdischarge in hospitalized patients with AECOPD. Int J Chron Obstruct Pulmon Dis. 2015;(10):2319–2325. https://doi.org/10.2147/COPD.S87091.

13. Moretti M. Erdosteine: its relevance in COPD treatment. Expert Opin Drug Metab Toxicol. 2009;5(3):333–343. https://doi.org/10.1517/17425250902814790.

14. Moretti M. Pharmacology and clinical efficacy of erdosteine in chronic obstructive pulmonary disease. Expert Rev Respir Med. 2007;1(3):307–316. https://doi.org/10.1586/17476348.1.3.307.

15. Cazzola M., Page C., Rogliani P., Calzetta L., Matera M.G. Multifaceted Beneficial Effects of Erdosteine: More than a Mucolytic Agent. Drugs. 2020;80(17):1799–1809. https://doi.org/10.1007/s40265-020-01412-x.

16. Hosoe H., Kaise T., Ohmori K., Isohama Y., Kai H., Takahama K., Miyata T. Mucolytic and antitussive effects of erdosteine. J Pharm Pharmacol. 1999;51(8):959–966. https://doi.org/10.1211/0022357991773230.

17. Hosoe H., Kaise T., Ohmori K. Erdosteine enhances mucociliary clearance in rats with and without airway inflammation. J Pharmacol Toxicol Methods. 1998;40(3):165–171. https://doi.org/10.1016/s1056-8719(98)00053-7.

18. Irwin R.S., Boulet L.P., Cloutier M.M., Fuller R., Gold P.M., Hoffstein V. et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest. 1998;114(2):133S–81S. https://doi.org/10.1378/chest.114.2_supplement.133s.

19. Bolser D.C. Cough suppressant and pharmacologic protussive therapy: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1):238S–249S. https://doi.org/10.1378/chest.129.1_suppl.238S.

20. Cazzola M., Calzetta L., Page C., Rogliani P., Matera M.G. Thiol-based drugs in pulmonary medicine: much more than mucolytics. Trends Pharmacol Sci. 2019;40(7):452–463. https://doi.org/10.1016/j.tips.2019.04.015.

21. Braga P.C., Dal Sasso M., Zuccotti T. Assessment of the antioxidant activity of the SH metabolite I of erdosteine on human neutrophil oxidative bursts. Arzneimittelforschung. 2000;50(8):739–746. https://doi.org/10.1055/s-0031-1300281.

22. Marabini L., Calò R., Braga P.C. Protective effect of erdosteine metabolite I against hydrogen peroxide-induced oxidative DNA-damage in lung epithelial cells. Arzneimittelforschung. 2011;61(12):700–706. https://doi.org/10.1055/s-0031-1300590.

23. Braga P.C., Culici M., Dal Sasso M., Falchi M., Spallino A. Free radical scavenging activity of erdosteine metabolite I investigated by electron paramagnetic resonance spectroscopy. Pharmacology. 2010;85(4):195–202. https://doi.org/10.1159/000275063.

24. Boyaci H., Maral H., Turan G., Başyiğit I., Dillioğlugil M.O., Yildiz F. et al. Effects of erdosteine on bleomycin-induced lung fibrosis in rats. Mol Cell Biochem. 2006;281(1–2):129–137. https://doi.org/10.1007/s11010-006-0640-3.

25. Demiralay R., Gürsan N., Ozbilim G., Erdogan G., Demirci E.. Comparison of the effects of erdosteine and N-acetylcysteine on apoptosis regulation in endotoxin-induced acute lung injury. J Appl Toxicol. 2006;26(4):301–308. https://doi.org/10.1002/jat.1133.

26. Erdem A., Gedikli E., Yersal N., Karaismailoglu S., Muftuoglu S., Fadillioglu E., Tuncer M. Protective role of erdosteine pretreatment on oleic acid-induced acute lung injury. J Surg Res. 2017;213:234–242. https://doi.org/10.1016/j.jss.2017.02.061.

27. Lee I.T., Yang C.M. Role of NADPH oxidase/ROS in pro-inflammatory mediators-induced airway and pulmonary diseases. Biochem Pharmacol. 2012;84(5):581–590. https://doi.org/10.1016/j.bcp.2012.05.005.

28. Basyigit I., Yildiz F., Cekmen M., Duman C., Bulut O. Effects of erdosteine on smoking-induced lipid peroxidation in healthy smokers. Drugs. 2005;6(2):83–89. https://doi.org/10.2165/00126839-200506020-00003.

29. Dal Negro R.W., Visconti M., Micheletto C., Tognella S. Changes in blood ROS, e-NO, and some pro-inflammatory mediators in bronchial secretions following erdosteine or placebo: a controlled study in current smokers with mild COPD. Pulm Pharmacol Ther. 2008;21(2):304–308. https://doi.org/10.1016/j.pupt.2007.07.004.

30. Dal Negro R.W., Visconti M. Erdosteine reduces the exercise-induced oxidative stress in patients with severe COPD: results of a placebo-controlled trial. Pulm Pharmacol Ther. 2016;(41):48–51. https://doi.org/10.1016/j.pupt.2016.09.007.

31. Park J.S., Park M.-Y., Cho Y.-J., Lee J.H., Yoo C.-G., Lee C.-T., Lee S.-M. Antiinflammatory effect of erdosteine in lipopolysaccharide-stimulated RAW 264.7 cells. Inflammation. 2016;39(4):1573–1581. https://doi.org/10.1007/s10753-016-0393-4.

32. Jang Y.Y., Song J.H., Shin Y.K., Han E.S., Lee C.S. Depressant effects of ambroxol and erdosteine on cytokine synthesis, granule enzyme release, and free radical production in rat alveolar macrophages activated by lipopolysaccharide. Pharmacol Toxicol. 2003;92(4):173–179. https://doi.org/10.1034/j.1600-0773.2003.920407.x.

33. Hayashi K., Hosoe H., Kaise T., Ohmori K. Protective effect of erdosteine against hypochlorous acid-induced acute lung injury and lipopolysaccharide-induced neutrophilic lung inflammation in mice. J Pharm Pharmacol. 2000;52(11):1411–1416. https://doi.org/10.1211/0022357001777414.

34. Demiralay R., Gürsan N., Erdem H. Regulation of sepsis-induced apoptosis of pulmonary cells by posttreatment of erdosteine and N-aceylcysteine. Toxicology. 2006;228(2–3):151–161. https://doi.org/10.1016/j.tox.2006.08.027.

35. Braga P.C., Dal Sasso M., Culici M., Verducci P., Lo Verso R., Marabini L. Effect of metabolite I of erdosteine on the release of human neutrophil elastase. Pharmacology. 2006;77(3):150–154. https://doi.org/10.1159/000094379.

36. Braga P.C., Dal Sasso M., Sala M.T., Gianelle V. Effects of erdosteine and its metabolites on bacterial adhesiveness. Arzneimittelforschung. 1999;49(4):344–350. https://doi.org/10.1055/s-0031-1300425.

37. Braga P.C., Zuccotti T., Dal Sasso M. Bacterial adhesiveness: effects of the SH metabolite of erdosteine (mucoactive drug) plus clarithromycin versus clarithromycin alone. Chemotherapy. 2001;47(3):208–214. https://doi.org/10.1159/000063223.

38. Dal Sasso M., Bovio C., Culici M., Braga P.C. The combination of the SH metabolite of erdosteine (a mucoactive drug) and ciprofloxacin increases the inhibition of bacterial adhesiveness achieved by ciprofloxacin alone. Drugs Exp Clin Res. 2002;28(2–3):75–82. Available at: https://pubmed.ncbi.nlm.nih.gov/12224380/.

39. Лазарева Н.Б., Максимов М.Л., Кукес И.В. Рациональная муколитическая терапия при респираторных заболеваниях: клиническая интерпретация фармакологических свойств для обоснованного выбора. Медицинский совет. 2021;(12):181–191. https://doi.org/10.21518/2079-701X-2021-12-181-191.

40. Marchioni C.F., Polu J.M., Taytard A., Hanard T., Noseda G., Mancini C. Evaluation of efficacy and safety of erdosteine in patients affected by chronic bronchitis during an infective exacerbation phase and receiving amoxycillin as basic treatment (ECOBES, European Chronic Obstructive Bronchitis Erdosteine Study). Int J Clin Pharmacol Ther. 1995;33(11):612–628. Available at: https://pubmed.ncbi.nlm.nih.gov/8688986/.

41. Aubier M., Berdah L. Multicenter, controlled, double-blind study of the efficacy and tolerance of Vectrine (erdostein) versus placebo in the treatment of stabilized chronic bronchitis with hypersecretion. Rev Mal Respir. 1999;16(4):521–528. Available at: https://pubmed.ncbi.nlm.nih.gov/10549062.

42. Crisafulli E., Coletti O., Costi S., Zanasi E., Lorenzi C., Lucic S. et al. Effectiveness of erdosteine in elderly patients with bronchiectasis and hypersecretion: a 15-day, prospective, parallel, open-label, pilot study. Clin Ther 2007;29(9):2001–2009. https://doi.org/10.1016/j.clinthera.2007.09.003.

43. Dal Negro R.W., Wedzicha J.A., Iversen M., Fontana G., Page C., Cicero A.F. et al. Effect of erdosteine on the rate and duration of COPD exacerbations: the RESTORE study. Eur Respir J. 2017;50(4):1700711. https://doi.org/10.1183/13993003.00711-2017.

44. Авдеев С.Н., Трушенко Н.В., Чикина С.Ю., Суворова О.А. Возможности терапии эрдостеином в снижении частоты обострений хронической обструктивной болезни легких. Пульмонология. 2022;32(2):253–259. https://doi.org/10.18093/0869-0189-2022-32-2-253-259.

45. Pizzino G., Irrera N., Cucinotta M., Pallio G., Mannino F., Arcoraci V. et al. Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev. 2017;2017:8416763. https://doi.org/10.1155/2017/8416763.

46. Dal Negro R., Visconti M., Trevisan F., Bertacco S., Micheletto C., Tognella S. Erdosteine enhances airway response to salbutamol in patients with mild-to-moderate COPD. Ther Adv Respir Dis. 2008;2(5):271–277. https://doi.org/10.1177/1753465808096109.

47. Dal Negro R.W., Visconti M., Tognella S., Micheletto C. Erdosteine affects eicosanoid production in COPD. Int J Clin Pharmacol Ther. 2011;49(1):41–45. https://doi.org/10.5414/cpp49041.

48. Cazzola M., Floriani I., Page C.P. The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data. Pulm Pharmacol Ther. 2010;23(2):135–144. https://doi.org/10.1016/j.pupt.2009.10.002.

49. Dal Negro R.W., Visconti M., Turco P. Efficacy of erdosteine 900 versus 600 mg/day in reducing oxidative stress in patients with COPD exacerbations: results of a double blind, placebo-controlled trial. Pulm Pharmacol Ther. 2015;33:47–51. https://doi.org/10.1016/j.pupt.2015.06.004.

50. Jenkins C.R., Postma D.S., Anzueto A.R., Make B.J., Peterson S., Eriksson G., Calverley P.M. Reliever salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease. BMC Pulm. Med. 2015;15:97. https://doi.org/10.1186/s12890-015-0077-0.

51. Авдеев С.Н. Значение мукоактивных препаратов в терапии ХОБЛ. РМЖ. Медицинское обозрение. 2015;(4):206–211. Режим доступа: https://www.rmj.ru/articles/obshchie-stati/Znachenie_mukoaktivnyh_preparatov_v_terapii_HOBL.

52. Tjandrawinata R.R., Nofiarny D., Mangunegoro H., Rahmawati I., Yunus F. The Role of Erdosteine in Reducing the Need for Bronchodilators During Acute Exacerbation of Chronic Obstructive Pulmonary Disease. J Indones Med Association. 2007;2007:337–345. Available at: https://www.research-gate.net/publication/279998781_The_role_of_erdosteine_in_reducing_the_need_for_bronchodilators_during_acute_exacerbation_of_chronic_obstructive_pulmonary_disease.

53. Calverley P.M., Page C., Dal Negro R.W., Fontana G., Cazzola M., Cicero A.F., Pozzi E., Wedzicha J.A. Effect of Erdosteine on COPD Exacerbations in COPD Patients with Moderate Airflow Limitation. Int J Chron Obstruct Pulmon Dis. 2019;14:2733–2744. https://doi.org/10.2147/COPD.S221852.

54. Decramer M., Rutten-van Mölken M., Dekhuijzen P.N.R., Troosters T., van Herwaarden C., Pellegrino R. et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365(9470):1552–1560. https://doi.org/10.1016/S0140-6736(05)66456-2.

55. Rogliani P., Matera M.G., Page C., Puxeddu E., Cazzola M., Calzetta L. Efficacy and safety profile of mucolytic/antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-acetylcysteine. Respir Res. 2019;20(1):104. https://doi.org/10.1186/s12931-019-1078-y.

56. Fraňová S., Kazimierová I., Pappová L., Molitorisová M., Jošková M., Šutovská M. The effect of erdosteine on airway defence mechanisms and inflammatory cytokines in the settings of allergic inflammation. Pulm Pharmacol Ther. 2019;(54):60–67. https://doi.org/10.1016/j.pupt.2018.11.006.

57. Sogut S., Ozyurt H., Armutcu F., Kart L., Iraz M., Akyol O. et al. Erdosteine prevents bleomycin-induced pulmonary fibrosis in rats. Eur J Pharmacol. 2004;494(2–3):213–220. https://doi.org/10.1016/j.ejphar.2004.04.045.

58. Yildirim Z., Kotuk M., Iraz M., Kuku I., Ulu R., Armutcu F., Ozen S. Attenuation of bleomycin-induced lung fibrosis by oral sulfhydryl containing antioxidants in rats: erdosteine and N-acetylcysteine. Pulm Pharmacol Ther. 2005;18(5):367–373. https://doi.org/10.1016/j.pupt.2005.02.001.

59. Guzel A., Kayhan S., Tutuncu S., Guzel A., Duran L., Alacam H. et al. Attenuation of bleomycin induced lung fibrosis by erdosteine and inhibition of the inducible nitric oxide synthase. Bratisl Lek Listy. 2015;116(3):196–202. https://doi.org/10.4149/bll_2015_039.