Ambroxol: A multifaceted molecule with additional therapeutic potentials in respiratory disorders of childhood

Expert Opinion on Drug Discovery

Volumn 6, Issue 11, 2011, Pages 1203-1214

  Paleari, Davide ^a   Rossi, Giovanni A ^b   Nicolini, Gabriele ^a   Olivieri, Dario ^c  

^a Medical Department   (Italy)

^b G GASLINI INSTITUTE   (Italy)

^c UNIVERSITY OF PARMA MEDICAL SCHOOL   (Italy)

Author keywords

ambroxol; anesthetic; anti inflammatory; antibacterial; antioxidant; antiviral; asthma; bacterial infection; biofilm; bronchiectasis; mucokinetic; mucus; oxygen radicals; respiratory virus; secretagogue; surfactant

Indexed keywords

AMBROXOL; SURFACTANT;

ANESTHESIA; ANTIBACTERIAL ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ANTIVIRAL ACTIVITY; CHILDHOOD DISEASE; HUMAN; MUCOLYSIS; NONHUMAN; PRIORITY JOURNAL; RESPIRATORY TRACT DISEASE; REVIEW;

EID: 80755175293     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2011.629646     Document Type: Review

References (103)

1. Disse BG. The pharmacology of ambroxol-review and new results. Eur J Respir Dis 1987;153(Suppl):255-62
2. Mezzetti M, Colombo L, Marini M, et al. A pharmacokinetic study on pulmonary tropism of ambroxol in patients under thoracic surgery. Eur J Emerg Surg Intensive Care 1990;13:179-85
3. Ren YC, Wang L, He HB, Tang X. Pulmonary selectivity and local pharmacokinetics of ambroxol hydrochloride dry powder inhalation in rat. J Pharm Sci 2009;98:1797-803
4. Houtmeyers E, Gosselink R, Gayan-Ramirez G, Decramer M. Effects of drugs on mucus clearance. Eur Respir J 1999;14:452-67 (Pubitemid 29461317)
5. Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respir Care 2007;52:1176-93
6. Gillissen A, Bartling A, Schoen S, Schulte-Werninghaus G. Antioxidant function of ambroxol in mononuclear and polymorphonuclear cells in vitro. Lung 1997;175:235-42 (Pubitemid 27260312)
7. Gillissen A, Scharling B, Jaworska M, et al. Oxidant scavenger function of ambroxol in vitro: a comparison with N-acetylcysteine. Res Exp Med 1997;196:386-98
8. Nowak D, Antezak A, Pietras T, et al. Protective effect of ambroxol against heat-and hydrogen peroxide-induced damage to lung lipids in mice. Eur Respir J 1994;7:1629-34 (Pubitemid 24294248)
9. Nowak D, Pierscinski G, Drzewoski J. Ambroxol inhibits doxorubicin-induced lipid peroxidation in heart of mice. Free Radic Biol Med 1995;19:659-63
10. Leffler A, Reckzeh J, Nau C. Block of sensory neuronal Na+ channels by the secretolytic ambroxol is associated with an interaction with local anaesthetic binding sites. Eur J Pharmacol 2010;630:19-28
11. 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;19:952-8 (Pubitemid 34567912)
12. Li F, Yu J, Yang H, et al. Effects of ambroxol on alginate of mature Pseudomonas aeruginosa biofilms. Curr Microbiol 2008;57:1-7
13. Halliday HL. Surfactants: past, present and future. J Perinatol 2008;28(Suppl 1):S47-56
14. Phelps DS. Surfactant regulation of host defense function in the lung: a question of balance. Pediatr Pathol Mol Med 2001;20:269-92 (Pubitemid 32577743)
15. Weaver TE, Conkright JJ. Function of surfactant proteins B and C. Ann Rev Physiol 2001;63:555-78
16. Chroneos ZC, Sever-Chroneos Z, Shepherd VL. Pulmonary surfactant: an immunological perspective. Cell Physiol Biochem 2010;25:13-26
17. Gil J, Thurnheer U. Morphometric evaluation of ultrastructural changes in type II alveolar cells of rat lung produced by bromhexine. Respiration 1971;28:438-56
18. von Wichert P, Bavendamm U, von Teichmann M, et al. Increased incorporation of fatty acids into phospholipids of lungs and livers of rabbits under the influence of bromhexine and ambroxol. Naunyn Schmiedebergs Arch Pharmacol 1977;297:269-73 (Pubitemid 8079428)
19. Malerba M, Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin Drug Metab Toxicol 2008;4:1119-29
20. Cerutti P, Kapanci Y. Effects of metabolite VIII of bromexine (Na 872) on type II epithelium of the lung: an experimental and morphological study with reference to surfactant secretion. Respiration 1979;37:241-51 (Pubitemid 9152417)
21. Laoag-Fernandez JB, Fernandez AM, Maruo T. Antenatal use of ambroxol for the prevention of infant respiratory distress syndrome. J Obstet Gynaecol Res 2000;26:307-12
22. Zhang ZQ, Huang XM, Lu H. Ambroxol for the prevention of respiratory distress syndrome in preterm infants: a meta analysis. Zhongguo Dang Dai Er Ke Za Zhi 2010;12:858-6
23. Hu Q, Lian JM, Li JQ. Efficacy of intravenous or atomizing ambroxol for prevention of respiratory distress syndrome in preterm infants. Zhongguo Dang Dai Er Ke Za Zhi 2006;8:301-3 (Pubitemid 44262904)
24. Seifart C, Clostermann U, Seifart U, et al. Cell-specific modulation of surfactant proteins by ambroxol treatment. Toxicol Appl Pharmacol 2005;203:27-35 (Pubitemid 40208363)
25. Myerburg MM, Harvey PR, Heidrich EM, et al. Acute regulation of the epithelial sodium channel in airway epithelia by proteases and trafficking. Am J Respir Cell Mol Biol 2010;43:712-19
26. Disse BG, Ziegler HW. Pharmacodynamic mechanism and therapeutic activity of ambroxol in animal experiments. Respiration 1987;51(Suppl 1):15-22 (Pubitemid 17070797)
27. Olivieri D, Del Donno M, Annicelli A, Palmieri F. Effect on themucociliary clearance of ambroxol administered via inhalation: preliminary observations. Arch Monaldi 1983;38:135-40
28. Yamaya M, Finkbeiner WE, Widdicombe JH. Ion transport by cultures of human tracheobronchial submucosal glands. Am J Physiol 1991;261(6 Pt 1):L485-90
29. Yamada T, Takemura Y, Niisato N, et al. Action of N-acylated ambroxol derivatives on secretion of chloride ions in human airway epithelia. Biochem Biophys Res Commun 2009;380:586-90
30. Wilson R, Dowling RB, Jackson AD. The biology of bacterial colonization and invasion of the respiratory mucosa. Eur Respir J 1996;9:1523-30 (Pubitemid 26233800)
31. Schraufstatter IU, Cochrane CG. Oxidants: types, sources, and mechanisms of injury. In: Crystal RG, West JB, editors. The lung, Scientific foundations. Raven Press; New York: 1991. p. 1803-10
32. Reddy SP. The antioxidant response element and oxidative stress modifiers in airway diseases. Curr Mol Med 2008;8:376-83
33. Rosias PP, Dompeling E, Hendriks HJ, et al. Exhaled breath condensate in children: pearls and pitfalls. Pediatr Allergy Immunol 2004;15:4-19 (Pubitemid 38327294)
34. Stetinova V, Herout V, Kvetina J. In vitro and in vivo antioxidant activity of ambroxol. Clin Exp Med 2004;4:152-8 (Pubitemid 40100911)
35. Rozniecki J, Nowak D. Protective effect of ambroxol on serum elastase inhibitory capacity against chloramine-T and cigarette smoke extract. Bull Eur Physiopathol Respir 1987;12:366s
36. Winsel K, Becher G. Effects of ambroxol on chemiluminescence of phagocytic cells and Na-arachidonate-induced bronchoconstriction in guinea-pigs. Eur Respir J 1992;5:289
37. Cho Y, Jang YY, Han ES, Lee CS. The inhibitory effect of ambroxol on hypochlorous acid-induced tissue damageand respiratory burst of phagocytic cells. Eur J Pharmacol 1999;383:83-91 (Pubitemid 29509826)
38. Lee CS, Jang YY, Song JS, et al. Ambroxol inhibits peroxynitrite-induced damage of alpha1-antiproteinase and free radical production in activated phagocytic cells. Pharmacol Toxicol 2002;91:140-9 (Pubitemid 35176683)
39. Kim HH, Jang YY, Han ES, Lee CS. Differential antioxidant effects of ambroxol, rutin, glutathione and harmaline. J Appl Pharmacol 1999;7:112-20
40. Park NH, Han ES, Lee CS. The inhibitory effect of ambroxol on respiratory burst, degranulation and cytosolic Ca2+ change in degraded immunoglobulin G-activated neutrophils. Pharmacol Toxicol 1999;84:81-7 (Pubitemid 29088368)
41. Nowak D, Pietras T, Antczak A, et al. Ambroxol inhibits endotoxin-induced lipid peroxidation in mice. Pol J Pharmacol 1993;45:317-22 (Pubitemid 23276704)
42. Zhao SP, Guo QL, Wang RK, Wang E. Oxidative and anti-oxidative effects of ambroxol on acute hydrochloric acid-induced lung injury in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2004;29:586-8
43. Donnini M, Luisetti M, Diomede L. Ambroxol reduces paraquat toxicity in the rat. In: Wichert von P, Miiller B, editors. Basic Research on Lung Surfactant. Progress in Respiratory Research; Karger, Basel: 1990. p. 329-32
44. Rossi GA, Balbi B, Benatti U, et al. Changes in pulmonary surfactant composition following MACC chemotherapy for lung carcinoma. Eur J Respir Dis 1987;71:400-9 (Pubitemid 18018875)
45. Nadeem A, Masood A, Siddiqui N. Oxidant-antioxidant imbalance in asthma: scientific evidence, epidemiological data and possible therapeutic options. Ther Adv Respir Dis 2008;2:215-35
46. Mello Filho AC, Hoffmann ME, Meneghini R. Cell killing and DNA damage by hydrogen peroxide are mediated by intracellular iron. Biochem J 1984;218:273-5 (Pubitemid 14190940)
47. Beeh KM, Beier J, Esperester A, Paul LD. Antiinflammatory properties of ambroxol. Eur J Med Res 2008;13:557-62
48. Stockley RA, Shaw J, Burnett D. Effect of ambroxol of neutrophil chemotaxis in vitro. Agents Actions 1988;24:292-6
49. Gibbs BF, Schmutzler W, Vollrath IB, et al. Ambroxol inhibits the release of histamine, leukotrienes and cytokines from human leukocytes and mast cells. Inflamm Res 1999;48:86-93 (Pubitemid 29110236)
50. Bianchi M, Mantovani A, Erroi A, et al. Ambroxol inhibits interleukin 1 and tumor necrosis factor production in human mononuclear cells. Agents Actions 1990;31:275-9
51. Pfeifer S, Zissel G, Kienast K, Muller-Quernheim J. Reduction of cytokine release of blood and bronchoalveolar mononuclear cells by ambroxol. Eur J Med Res 1997;2:129-32
52. Betz R. Glucocorticoids and ambroxol inhibit secretion of inflammatory cytokines in tracheobronchial epithelial cells: possible role of NF-kappa B transcription factor. Pneumologie 1997;51:491-2
53. Su X, Wang L, Song Y, Bai C. Inhibition of inflammatory responses by ambroxol, a mucolytic agent, in a murine model of acute lung injury induced by lipopolysaccharide. Intensive Care Med 2004;30:133-40 (Pubitemid 38147119)
54. Utsugi M, Dobashi K, Koga Y, et al. Ambroxol inhibits platelet-derived growth factor production in human monocytic cells. Eur J Pharmacol 2002;436:47-51 (Pubitemid 34142396)
55. Gibbs BF. Differential modulation of IgE-dependent activation of human basophils by ambroxol and related secretolytic analogues. Int J Immunopathol Pharmacol 2009;22:919-27
56. Ferretti C, Coppi G, Blengio M, Genazzani E. Inhibitory effect of theophylline, theophylline-7-acetic acid, ambroxol and ambroxol-theophylline-7- acetate on rat lung cAMP phosphodiesterase isoenzymes. Int J Tissue React 1992;14:31-6
57. Jin SL, Goya S, Nakae S, et al. Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol 2010;126:1252-9
58. Tenner AL, Robinson SL, Borchelt J, Wright JR. Human pulmonary surfactantprotein (SP-A), a protein structurally homologous to C1q, can enhance FcR- and CR1-mediated phagocytosis. J Biol Chem 1989;263:13923-8 (Pubitemid 19198488)
59. Kido H, Sakai K, Kishino Y, Tashiro M. Pulmonary surfactant is a potential endogenous inhibitor of proteolytic activation of Sendai virus and influenza A virus. FEBS Lett 1993;322:115-19 (Pubitemid 23140359)
60. Peterhans E. Oxidants and antioxidants in viral diseases: disease mechanisms and metabolic regulation. J Nutr 1997;127(5 Suppl):962-5
61. Nencioni L, Sgarbanti R, De Chiara G, et al. Influenza virus and redox mediated cell signaling: a complex network of virus/host interaction. New Microbiol 2007;30:367-75 (Pubitemid 350183835)
62. Suliman HB, Ryan LK, Bishop L, Folz RJ. Prevention of influenza-induced lung injury in mice overexpressing extracellular superoxide dismutase. Am J Physiol Lung Cell Mol Physiol 2001;280:69-78
63. Castro SM, Guerrero-Plata A, Suarez-Real G, et al. Antioxidant treatment ameliorates respiratory syncytial virus-induced disease and lung inflammation. Am J Respir Crit Care Med 2006;174:1361-9 (Pubitemid 44913038)
64. Nobata K, Fujimura M, Ishiura Y, et al. Ambroxol for the prevention of acute upper respiratory disease. Clin Exp Med 2006;6:79-83
65. Niederman MS. Bacterial adherence as a mechanism of airway colonization. Eur J Clin Microbiol Infect Dis 1989;8:15-20 (Pubitemid 19041444)
66. Hafez MM, Aboulwafa MM, Yassien MA, Hassouna NA. Activity of some mucolytics against bacterial adherence to mammalian cells. Appl Biochem Biotechnol 2009;158:97-112
67. Ndour CT, Ahmed K, Nakagawa T, et al. Modulating effects of mucoregulating drugs on the attachment of Haemophilus influenzae. Microb Pathog 2001;30:121-7 (Pubitemid 32552993)
68. Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science 1999;284:1318-22 (Pubitemid 29289651)
69. Fick RB Jr, Sonoda F, Hornick D B. Emergence and persistence of Pseudomonas aeruginosa in the cystic fibrosis airway. Semin Respir Infect 1992;7:168-78 (Pubitemid 23014528)
70. Lu Q, Yu J, Yang X, et al. Ambroxol interferes with Pseudomonas aeruginosa quorum sensing. Int J Antimicrob Agents 2010;36:211-15
71. Principi N, Zavattini G, Daniotti S. Possibility of interaction among antibiotics and mucolytics in children. Int J Clin Pharmacol Res 1986;6:369-72 (Pubitemid 17197480)
72. Fraschini F, Scaglione F, Scarpazza G, et al. Effects of a mucolytic agent on the bioavailability of antibiotics in patients with chronic respiratory diseases. Curr Ther Res 1988;43:734-42
73. Wiemeyer JC. Influence of ambroxol on the bronchopulmonary level of antibiotics. Arzneimittelforschung 1981;31:974-6 (Pubitemid 11117100)
74. Spatola J, Poderoso JJ, Wiemeyer JC, et al. Influence of ambroxol on lung tissue penetration of amoxicillin. Arzneimittelforschung 1987;37:965-6 (Pubitemid 17135347)
75. Gene R, Poderoso JJ, Corazza C, et al. Influence of ambroxol on amoxicillin levels in bronchoalveolar lavage fluid. Arzneimittelforschung 1987;37:967-8 (Pubitemid 17135348)
76. Ossipov MH, Porreca F. Challenges in the development of novel treatment strategies for neuropathic pain. NeuroRx 2005;2:650-61 (Pubitemid 41393272)
77. Weiser T. Ambroxol: a CNS drug? CNS Neurosci Ther 2008;14:17-24
78. Fischer J, Pschorn U, Vix JM, et al. Efficacy and tolerability of ambroxol hydrochloride lozenges in sore throat. Randomised, double-blind, placebo-controlled trials regarding the local anaesthetic properties. Arzneimittelforschung 2002;52:256-63 (Pubitemid 34438223)
79. de Mey C, Peil H, Kolsch S, et al. Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat. Arzneimittelforschung Drug Res2008;58:557-68
80. Weiser T, Wilson N. Inhibition of tetrodotoxin (TTX)-resistant and TTX-sensitive neuronal Na(+) channels by the secretolytic ambroxol. Mol Pharmacol 2002;62:433-8 (Pubitemid 36329359)
81. Roza C, Laird JM, Souslova V, et al. The tetrodotoxin resistant Na+ channel NaV1.8 is essential for the expression of spontaneous activity in damaged sensory axons of mice. J Physiol 2003;550:921-6 (Pubitemid 37010074)
82. Jarvis MF, Honore P, Shieh CC, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci USA 2007;104:8520-5 (Pubitemid 47175520)
83. Weiser T. Comparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels. Neurosci Lett 2006;395:179-84 (Pubitemid 43213140)
84. Gaida W, Klinder K, Arndt K, Weiser T. Ambroxol, a Nav1.8-preferring Na(+) channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. Neuropharmacology 2005;49:1220-7 (Pubitemid 41608646)
85. Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS). Specialties mucolytiques (carbocisteine, acetylcisteine), mucofluidificantes (benzoate de meglumine) administrees par voie orale et de l'helicidine: contre-indication, chez le nourisson - Lettre aux professionnels de sante. April 24, 2010. Available from: http://www.afssaps.fr/Infos-de-securite/ Lettres-aux-professionnels-de-sante/ Specialites-mucolytiques- carbocisteineacetylcysteine- mucofluidifiantes-benzoatede- meglumine- administrees-par-voieorale- et-l-helicidine-contre-indicationchez- le-nourrisson-Lettre-auxprofessionnels- de-sante [Accessed on 29 June 2011]
86. Agenzia Italiana del Farmaco (AIFA). Nota informativa importante: Mucolitici per uso orale e rettale: controindicazione nei bambini al di sotto dei 2 anni. November 2010. Available from: http://www. agenziafarmaco.gov.it/ sites/ default/files/nii-mucolitici-aifa- versione-definitiva-17.11.2010-.pdf [Accessed on 29 June 2011]
87. Schulz M, Hammerlein A, Hinkel U, et al. Safety and usage pattern of an over-the-counter ambroxol cough syrup: a community pharmacy-based cohortstudy. Int J Clin Pharmacol Ther 2006;44:409-21 (Pubitemid 44696432)
88. Weinmann HM. Ambroxol (Mucosolvan) in paediatrics. Clinical results with different forms of administration. Therapiewoche (Karlsruhe) 1981;31:7940-7
89. Miyazaki S, Kubo W, Itoh K, et al. The effect of taste masking agents on in situ gelling pectin formulations for oral sustained delivery of paracetamol and ambroxol. Int J Pharm 2005;297:38-49 (Pubitemid 40720264)
90. Fluibron per Aerosol™, Chiesi Farmaceutici S.p.A., Parma, Italy
91. Vytiska-Binstorfer E, Salzer H, Simbruner G. Ambroxol in comparison with betamethasone for the stimulation of antepartal lung maturity. A clinical double-blind study. Zentralbl Gynakol 1986;108:220-9 (Pubitemid 16091057)
92. Fegiz G. Prevention by ambroxol of bronchopulmonary complications after upper abdominal surgery: double-blind Italian multicenter clinical study versus placebo. Lung 1991;169:69-76
93. Careddu P, Zavattini G. Mucosolvan® (ambroxol) in pediatric use - Controlled clinical trial vs acetylcysteine. Asthma Branch Emphys 1984;4:23-6
94. Baldini G, Gucci M, Taro D, et al. Controlled clinical study of a new ambroxol formula in the treatment of infantile spastic bronchitis. Minerva Pediatr 1989;41:91-5 (Pubitemid 19109589)
95. Ratjen F, Wonne 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;144:374-8 (Pubitemid 16194459)
96. Romano C, Gargani GF, Minicucci L, Natron M. Controlled clinical study on the activity of a new mucoregulating drug in obstructive bronchial pathology with a marked hypersecretory feature. The pediatric experience. Minerva Pediatr 1984;36:127-38
97. Nash EF, Stephenson A, Ratjen F, Tullis E. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev 2009;21(1):CD007168
98. 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;17:27-34 (Pubitemid 37468406)
99. Busse WW, Lemanske RF Jr, Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet 2010;376:826-34
100. Passali D, Zavattini G. Multicenter study on the treatment of secretory otitis media with ambroxol. Importance of a surface-tension-lowering substance. Respiration 1987;51(Suppl 1):52-9 (Pubitemid 17070802)
101. Golusinski W, Szmeja Z, Szyfter W. The use of mucolytic preparations (Mucosolvan) in nasal and paranasal sinuses in children. Otolaryngol Pol 1996;50:599-606
102. Moscoso M, Garcia E, Lopez R. Pneumococcal biofilms. Int Microbiol 2009;12(2):77-85
103. Marchisio P, Ghisalberti E, Fusi M, et al. Paranasal sinuses and middle ear infections: what do they have in common? Pediatr Allergy Immunol 2007;18(Suppl 18):31-4 (Pubitemid 47340818)