Рациональная муколитическая терапия амброксолом: спорное и бесспорное

Бабак С.Л., Горбунова М.В., Малявин А.Г. Рациональная муколитическая терапия амброксолом: спорное и бесспорное. Consilium Medicum. 2023;25(9):623–628. DOI: 10.26442/20751753.2023.9.202405

© ООО «КОНСИЛИУМ МЕДИКУМ», 2023 г.

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Babak SL, Gorbunova MV, Malyavin AG. Rational mucolytic therapy with ambroxol: controversial and indisputable. A review. Consilium Medicum. 2023;25(9):623–628. DOI: 10.26442/20751753.2023.9.202405

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Аннотация

Многолетний опыт применения амброксола основан на его возможности регулировать базовые механизмы физиологической продукции и транспорта бронхиальной слизи. Основным показанием для амброксола является муколитическая терапия острых и хронических бронхолегочных заболеваний, ассоциированных с гиперсекрецией и нарушением транспорта слизи. Амброксол обладает рядом следующих свойств: высокая секретолитическая активность (способствует клиренсу слизи, облегчает отхаркивание мокроты, уменьшает продуктивный кашель); противовоспалительная и антиоксидантная активность; локальный обезболивающий (анестетический) эффект посредством блокады натриевых каналов клеточных мембран. Эффект анестезии слизистых оболочек относят к новому фармакологическому действию амброксола, полезному в терапии острых инфекций дыхательных путей. Эффективность и безопасность применения амброксола в клинической практике подтверждена полувековым опытом его назначения. Целью настоящей публикации явилась актуальная оценка спорных и бесспорных химических, фармакологических, клинических данных о свойствах амброксола в концепции современной «восстановительной муколитической терапии», способной улучшить терапию и прогноз пациентов, имеющих гиперсекрецию трахеобронхиального секрета, нарушения мукоцилиарного клиренса и непродуктивный кашель.

Ключевые слова: амброксол, мукоцилиарный клиренс, трахеобронхиальный секрет, секретолитическая активность, мукокинетическая активность, муколитическая терапия, непродуктивный кашель

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Many years of experience in the use of ambroxol is based on its ability to regulate the basic mechanisms of physiological production and transport of bronchial mucus. The main indication for ambroxol is the mucolytic therapy of acute and chronic bronchopulmonary diseases associated with hypersecretion and impaired mucus transport. Ambroxol has a number of the following properties: high secretolytic activity (promotes mucus clearance, facilitates expectoration of sputum, reduces productive cough); anti-inflammatory and antioxidant activity; local analgesic (anesthetic) effect through the blockade of sodium channels of cell membranes. The effect of anesthesia of the mucous membranes is attributed to the new pharmacological action of ambroxol, useful in the treatment of acute respiratory tract infections. The efficacy and safety of ambroxol in clinical practice has been confirmed by half a century of experience in its administration. The purpose of this publication was an up-to-date assessment of the controversial and indisputable chemical, pharmacological, clinical data on the properties of ambroxol in the concept of modern “recovery mucolytic therapy” that can improve the therapy and prognosis of patients with tracheobronchial secretion hypersecretion, impaired mucociliary clearance and unproductive cough.

Keywords: ambroxol, mucociliary clearance, tracheobronchial secretion, secretolytic activity, mucokinetic activity, mucolytic therapy, nonproductive cough

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Список литературы

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3. Prevention of chronic bronchitis exacerbations with ambroxol (mucosolvan retard). An open, long-term, multicenter study in 5,635 patients. Respiration. 1989;55(Suppl.):84-96.
4. Malerba M, Ponticiello A, Radaeli A, et al. Effect of twelve-months therapy with oral ambroxol in preventing exacerbations in patients with COPD. Double-blind, randomized, multicenter, placebo-controlled study (the AMETHIST Trial). Pulm Pharmacol Ther. 2004;17(1):27-34. DOI:10.1016/j.pupt.2003.08.004
5. Ratjen F, Wönne R, Posselt HG, et al. A double-blind placebo controlled trial with oral ambroxol and N-acetylcysteine for mucolytic treatment in cystic fibrosis. Eur J Pediatr. 1985;144(4):374-8. DOI:10.1007/BF00441781
6. Baranwal AK, Murthy AS, Singhi SC. High-dose Oral Ambroxol for Early Treatment of Pulmonary Acute Respiratory Distress Syndrome: an Exploratory, Randomized, Controlled Pilot Trial. J Trop Pediatr. 2015;61(5):339-50. DOI:10.1093/tropej/fmv033
7. Aleksa VI, Prozorova VK, Mal'tseva NA, Shatikhina LN. Effectiveness of lasolvan in patients with chronic obstructive bronchitis and non-atopic bronchial asthma. Terapevticheskii Arkhiv (Ter. Arkh.). 2001;73(3):48-51.
8. Шмелева Н.М. Мукорегулирующая терапия при заболеваниях органов дыхания: возможности амброксола. Consilium Medicum. 2012;14(11):7-11 [Shmeleva NM. Mukoreguliruyushchaia terapiia pri zabolevaniiakh organov dykhaniia: vozmozhnosti ambroksola. Consilium Medicum. 2012;14(11):7-11 (in Russian)].
9. Cavalu S, Sharaf H, Saber S, et al. Ambroxol, a mucolytic agent, boosts HO-1, suppresses NF-κB, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis. FASEB J. 2022;36(9):e22496. DOI:10.1096/fj.202200749R
10. Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery: double-blind Italian multicenter clinical study versus placebo. Lung. 1991;169(2):69-76. DOI:10.1007/BF02714144
11. Hashizume T. Pulmonary alveolar proteinosis successfully treated with ambroxol. Intern Med. 2002;41(12):1175-8. DOI:10.2169/internalmedicine.41.1175
12. Yoshida S, Yokohira M, Yamakawa K, et al. Effects of the expectorant drug ambroxol hydrochloride on chemically induced lung inflammatory and neoplastic lesions in rodents. J Toxicol Pathol. 2018;31(4):255-65. DOI:10.1293/tox.2018-0012
13. Malerba M, Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin Drug Metab Toxicol. 2008;4(8):1119-29. DOI:10.1517/17425255.4.8.1119
14. Guo Z, Chen Y, Ding X, et al. Simultaneous determination of ambroxol and salbutamol in human plasma by ultra-performance liquid chromatography-tandem mass spec-trometry and its application to a pharmacokinetic study. Biomed Chromatogr. 2016;30(11):1789-95. DOI:10.1002/bmc.3754
15. Jauch R, Bozler G, Hammer R, et al. Ambroxol, studies of biotransformation in man and determination in biological samples (author's transl). Arzneimittelforschung.
1978;28(5a):904-11.
16. Ishiguro N, Senda C, Kishimoto W, et al. Identification of CYP3A4 as the predominant isoform responsible for the metabolism of ambroxol in human liver microsomes. Xenobiotica. 2000;30(1):71-80.
17. Pueschmann S, Engelhorn R. Pharmacological study on the bromhexine metabolite am-broxol (author's transl). Arzneimittelforschung. 1978;28(5a):889-98.
18. Miyata T, Kai H, Saito M, et al. Effects of am-broxol on pulmonary surfactant – analysis of the fatty acid composition of phosphatidylcho-line in the sputum and normal respiratory tract fluid in rabbits. Nihon Yakurigaku Zasshi. 1986;88(1):57-64.
19. Kyle H, Robinson NP, Widdicombe JG. Mucus secretion by tracheas of ferret and dog. Eur J Respir Dis. 1987;70(1):14-22.
20. IravaniJ, Melville GN. Mucociliary function of the respiratory tract as influenced by drugs. Respiration. 1974;31(4):350-7.
21. Bossi R, Braga PC, Allegra L. Ambroxol and mucociliary transport. Arch Monaldi. 1984;39(3):227-33 (in Italian).
22. Wirtz HR. Effect of ambroxol on surfactant secretion and synthesis in isolated type II alveolar cells. Pneumologie. 2000;54(7):278-83. DOI:10.1055/s-2000-4452
23. Tahvanainen J, Hallman M. Surfactant abnormality after endotoxin-induced lung injury in guinea-pigs. Eur J Respir Dis. 1987;71(4):250-8.
24. Dauberschmidt R, Kuckelt W, Bender V, et al. Effects of bromhexine metabolite VIII (NA 872) in an animal model of the respir-atory distress syndrome. Bull Eur Physiopathol Respir. 1980;16(2):135-43.
25. Jang YY, Song JH, Shin YK, et al. 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):173-9.
26. Ottonello L, Arduino N, Bertolotto M, et al. In vitro inhibition of human neutrophil histotoxicity by ambroxol: evidence for a multistep mechanism. Br J Pharmacol. 2003;140(4):736-42. DOI:10.1038/sj.bjp.0705497
27. Fois G, Hobi N, Felder E, et al. A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca² release from acidic Ca² stores. Cell Calcium.
2015;58(6):628-37. DOI:10.1016/j.ceca.2015.10.002
28. Koyama I, Matsunaga T, Harada T, et al. Ambroxol reduces LPS toxicity mediated by induction of alkaline phosphatases in rat lung. Clin Biochem. 2004;37(8):688-93. DOI:10.1016/j.clinbiochem.2004.02.004
29. Yang B, Yao DF, Ohuchi M, et al. Ambroxol suppresses influenza-virus proliferation in the mouse airway by increasing antiviral factor levels. Eur Respir J. 2002;19(5):952-8.
30. Leffler A, Reckzeh J, Nau C. Block of sensory neuronal Na+ channels by the secreolytic ambroxol is associated with an interaction with local anesthetic binding sites. Eur J Pharmacol. 2010;630(1-3):19-28. DOI:10.1016/j.ejphar.2009.12.027
31. Guerra-Farfan E, Garcia-Sanchez Y, Jornet-Gibert M, et al. Clinical practice guidelines: The good, the bad, and the ugly. Injury. 2023;54 Suppl. 3:S26-9. DOI:10.1016/j.injury.2022.01.047
32. Poole P, Sathananthan K, Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;5(5):CD001287. DOI:10.1002/14651858.CD001287.pub6
33. Papadopoulou E, Hansel J, Lazar Z, et al. Mucolytics for acute exacerbations of chronic obstructive pulmonary disease: a meta-analysis. Eur Respir Rev. 2023;32(167):220141. DOI:10.1183/16000617.0141-2022
34. Cazan D, Klimek L, Sperl A, et al. Safety of ambroxol in the treatment of airway diseases in adult patients. Expert Opin Drug Saf. 2018;17(12):1211-224. DOI:10.1080/14740338.2018.1533954
35. Kantar A, Klimek L, Cazan D, et al. An overview of efficacy and safety of ambroxol for the treatment of acute and chronic respiratory diseases with a special regard to children. Multidiscip Respir Med. 2020;15(1):511. DOI:10.4081/mrm.2020.511

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1. Houtmeyers E, Gosselink R, Gayan-Ramirez G, Decramer M. Effects of drugs on mucus clear-ance. Eur Respir.J. 1999;14(2):452-67.
2. Zaitsev AA, Leshchenko IV, Esaulova NA, Viktorova IA. Evaluation of the efficacy and safety of a combination drug containing ambroxol, guaifenesin, and levosalbutamol versus a fixed-dose combination of bromhexine/guaifenesin/salbutamol in the treatment of productive cough in adult patients with acute bronchitis. Terapevticheskii Arkhiv (Ter. Arkh.). 2023;95(3):236-24 (in Russian). DOI:10.26442/00403660.2023.03.202099
3. Prevention of chronic bronchitis exacerbations with ambroxol (mucosolvan retard). An open, long-term, multicenter study in 5,635 patients. Respiration. 1989;55(Suppl.):84-96.
4. Malerba M, Ponticiello A, Radaeli A, et al. Effect of twelve-months therapy with oral ambroxol in preventing exacerbations in patients with COPD. Double-blind, randomized, multicenter, placebo-controlled study (the AMETHIST Trial). Pulm Pharmacol Ther. 2004;17(1):27-34. DOI:10.1016/j.pupt.2003.08.004
5. Ratjen F, Wönne R, Posselt HG, et al. A double-blind placebo controlled trial with oral ambroxol and N-acetylcysteine for mucolytic treatment in cystic fibrosis. Eur J Pediatr. 1985;144(4):374-8. DOI:10.1007/BF00441781
6. Baranwal AK, Murthy AS, Singhi SC. High-dose Oral Ambroxol for Early Treatment of Pulmonary Acute Respiratory Distress Syndrome: an Exploratory, Randomized, Controlled Pilot Trial. J Trop Pediatr. 2015;61(5):339-50. DOI:10.1093/tropej/fmv033
7. Aleksa VI, Prozorova VK, Mal'tseva NA, Shatikhina LN. Effectiveness of lasolvan in patients with chronic obstructive bronchitis and non-atopic bronchial asthma. Terapevticheskii Arkhiv (Ter. Arkh.). 2001;73(3):48-51.
8. Shmeleva NM. Mukoreguliruyushchaia terapiia pri zabolevaniiakh organov dykhaniia: vozmozhnosti ambroksola. Consilium Medicum. 2012;14(11):7-11 (in Russian).
9. Cavalu S, Sharaf H, Saber S, et al. Ambroxol, a mucolytic agent, boosts HO-1, suppresses NF-κB, and decreases the susceptibility of the inflamed rat colon to apoptosis: A new treatment option for treating ulcerative colitis. FASEB J. 2022;36(9):e22496. DOI:10.1096/fj.202200749R
10. Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery: double-blind Italian multicenter clinical study versus placebo. Lung. 1991;169(2):69-76. DOI:10.1007/BF02714144
11. Hashizume T. Pulmonary alveolar proteinosis successfully treated with ambroxol. Intern Med. 2002;41(12):1175-8. DOI:10.2169/internalmedicine.41.1175
12. Yoshida S, Yokohira M, Yamakawa K, et al. Effects of the expectorant drug ambroxol hydrochloride on chemically induced lung inflammatory and neoplastic lesions in rodents. J Toxicol Pathol. 2018;31(4):255-65. DOI:10.1293/tox.2018-0012
13. Malerba M, Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin Drug Metab Toxicol. 2008;4(8):1119-29. DOI:10.1517/17425255.4.8.1119
14. Guo Z, Chen Y, Ding X, et al. Simultaneous determination of ambroxol and salbutamol in human plasma by ultra-performance liquid chromatography-tandem mass spec-trometry and its application to a pharmacokinetic study. Biomed Chromatogr. 2016;30(11):1789-95. DOI:10.1002/bmc.3754
15. Jauch R, Bozler G, Hammer R, et al. Ambroxol, studies of biotransformation in man and determination in biological samples (author's transl). Arzneimittelforschung.
1978;28(5a):904-11.
16. Ishiguro N, Senda C, Kishimoto W, et al. Identification of CYP3A4 as the predominant isoform responsible for the metabolism of ambroxol in human liver microsomes. Xenobiotica. 2000;30(1):71-80.
17. Pueschmann S, Engelhorn R. Pharmacological study on the bromhexine metabolite am-broxol (author's transl). Arzneimittelforschung. 1978;28(5a):889-98.
18. Miyata T, Kai H, Saito M, et al. Effects of am-broxol on pulmonary surfactant – analysis of the fatty acid composition of phosphatidylcho-line in the sputum and normal respiratory tract fluid in rabbits. Nihon Yakurigaku Zasshi. 1986;88(1):57-64.
19. Kyle H, Robinson NP, Widdicombe JG. Mucus secretion by tracheas of ferret and dog. Eur J Respir Dis. 1987;70(1):14-22.
20. IravaniJ, Melville GN. Mucociliary function of the respiratory tract as influenced by drugs. Respiration. 1974;31(4):350-7.
21. Bossi R, Braga PC, Allegra L. Ambroxol and mucociliary transport. Arch Monaldi. 1984;39(3):227-33 (in Italian).
22. Wirtz HR. Effect of ambroxol on surfactant secretion and synthesis in isolated type II alveolar cells. Pneumologie. 2000;54(7):278-83. DOI:10.1055/s-2000-4452
23. Tahvanainen J, Hallman M. Surfactant abnormality after endotoxin-induced lung injury in guinea-pigs. Eur J Respir Dis. 1987;71(4):250-8.
24. Dauberschmidt R, Kuckelt W, Bender V, et al. Effects of bromhexine metabolite VIII (NA 872) in an animal model of the respir-atory distress syndrome. Bull Eur Physiopathol Respir. 1980;16(2):135-43.
25. Jang YY, Song JH, Shin YK, et al. 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):173-9.
26. Ottonello L, Arduino N, Bertolotto M, et al. In vitro inhibition of human neutrophil histotoxicity by ambroxol: evidence for a multistep mechanism. Br J Pharmacol. 2003;140(4):736-42. DOI:10.1038/sj.bjp.0705497
27. Fois G, Hobi N, Felder E, et al. A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca² release from acidic Ca² stores. Cell Calcium.
2015;58(6):628-37. DOI:10.1016/j.ceca.2015.10.002
28. Koyama I, Matsunaga T, Harada T, et al. Ambroxol reduces LPS toxicity mediated by induction of alkaline phosphatases in rat lung. Clin Biochem. 2004;37(8):688-93. DOI:10.1016/j.clinbiochem.2004.02.004
29. Yang B, Yao DF, Ohuchi M, et al. Ambroxol suppresses influenza-virus proliferation in the mouse airway by increasing antiviral factor levels. Eur Respir J. 2002;19(5):952-8.
30. Leffler A, Reckzeh J, Nau C. Block of sensory neuronal Na+ channels by the secreolytic ambroxol is associated with an interaction with local anesthetic binding sites. Eur J Pharmacol. 2010;630(1-3):19-28. DOI:10.1016/j.ejphar.2009.12.027
31. Guerra-Farfan E, Garcia-Sanchez Y, Jornet-Gibert M, et al. Clinical practice guidelines: The good, the bad, and the ugly. Injury. 2023;54 Suppl. 3:S26-9. DOI:10.1016/j.injury.2022.01.047
32. Poole P, Sathananthan K, Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;5(5):CD001287. DOI:10.1002/14651858.CD001287.pub6
33. Papadopoulou E, Hansel J, Lazar Z, et al. Mucolytics for acute exacerbations of chronic obstructive pulmonary disease: a meta-analysis. Eur Respir Rev. 2023;32(167):220141. DOI:10.1183/16000617.0141-2022
34. Cazan D, Klimek L, Sperl A, et al. Safety of ambroxol in the treatment of airway diseases in adult patients. Expert Opin Drug Saf. 2018;17(12):1211-224. DOI:10.1080/14740338.2018.1533954
35. Kantar A, Klimek L, Cazan D, et al. An overview of efficacy and safety of ambroxol for the treatment of acute and chronic respiratory diseases with a special regard to children. Multidiscip Respir Med. 2020;15(1):511. DOI:10.4081/mrm.2020.511

Авторы

С.Л. Бабак*, М.В. Горбунова, А.Г. Малявин

ФГБОУ ВО «Московский государственный медико-стоматологический университет им. А.И. Евдокимова» Минздрава России, Москва, Россия
*sergbabak@mail.ru

________________________________________________

Sergey L. Babak*, Marina V. Gorbunova, Andrey G. Malyavin

Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russia
*sergbabak@mail.ru

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