Natural remedies for acute post-viral cough in children

Main Article Content

Vitalia Murgia
Giorgio Ciprandi
Martina Votto
Maria De Filippo
Maria Angela Tosca
Gian Luigi Marseglia

Keywords

glycerol, herbal medicines, honey, natural compounds, post-viral acute cough

Abstract

The post-viral acute cough is the most common symptom in childhood. Consequently, the use of cough relievers is frequent. Many products for treating cough contain natural components. An ancient tradition has always established herbal medicine and honey as effective and safe means to relieve cough. Nevertheless, very few studies adequately investigated the real effectiveness and safety of natural products in treating acute cough. There is some evidence, provided by pediatric randomized controlled trials, about honey, one multicomponent product (containing Plantagolanceolata, Grindelia robusta, Helichrysum italicum, and honey), and Pelargonium sidoides. Other group of substances, including glycerol and isolated natural compounds, can help manage cough but robust evidence still lacks in children. There is an urgent need to perform rigorous studies that confirm the natural products’ efficacy and safety for relieving post-viral acute cough.

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References

1. Chang AB, Oppenheimer JJ, Irwin RS. Managing chronic cough as a symptom in children and management algorithms. Chest. 2020;S0012-3692(20):30325-1. 10.1016/j.chest.2020.01.042

2. Galway NC, Shields MD. The child with an incessant dry cough. Pediatr Res Rev. 2019;30:58–64. 10.1016/j.prrv.2018.08.002

3. Finley CR, Chan DS, Garrison S, Korownyk C, Kolber MR, Campbell S, et al. What are the most common conditions in primary care? Can Fam Phys. 2018;64:832–40. PMid: 30429181

4. Derebery MJ, Dicpinigaitis PV. New horizons: Current and potential future self-treatments for acute upper respiratory tract conditions. Postgrad Med. 2013;125:82–96. 10.3810/pgm.2013.01.2605

5. Degeorge KC, Ring DJ, Dalrymple SN. Treatment of the common cold. Am Fam Phy. 2019;100:281–9. PMid: 31478634.

6. Goldman RD. Treating cough and cold: Guidance for caregivers of children and youth. Paediatr Child Health. 2011;16:564–6. 10.1093/pch/16.9.564

7. Paul IM. Therapeutic options for acute cough due to upper respiratory infections in children. Lung. 2012;190:41–4. 10.1007/s00408-011-9319-y

8. Wagner L, Cramer H, Klose P, Lauche R, Gass F, Dobos G, et al. Herbal medicine for cough: A systematic review and meta-analysis. Forsch Komplem. 2015;22:359–68. 10.1159/000442111

9. Morice AH. Over-the-counter cough medicines: New approaches. Pulm Pharmacol Therap. 2015;1–3. 10.1016/j.pupt.2015.07.006

10. Begic E, Begic Z, Dobraca A, Hasanbegovic E. Productive cough in children and adolescents–View from primary health care system. Med Arch. 2017;71:66–8. 10.5455/medarh.2017.71.66-68

11. Worker PM, Schwermer M, Sommer S, Langler A, Fetz K, Ostermann T, et al. Complementary and alternative medicine in the treatment of acute bronchitis in children: A systematic review. Compl Therp Med. 2019;49:102217. 10.1016/j.ctim.2019.102217

12. Turan C, Yurtseven A, Saz EU. Physician’s prescription pattern in young infants with upper respiratory infections/ cough and cold in emergency department. Pak J Med Sci. 2020;36:166–71. 10.12669/pjms.36.2.1240

13. Barth A, Hovhannnisyan A, Jamalyan K, Narimanyan M. Antitussive effect of a fixed combination of Justicia adhatoda, Echinacea purpurea, and Eleutherococcus senticosus extracts in patients with acute upper respiratory tract infection: A comparative, randomized, double-blind, placebo-controlled study. Phytomedicine. 2015;22:1195–1200. 10.1016/j.phymed.2015.10.001

14. Smith SM, Schroeder K, Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in community settings. Cochrane Database Syst Rev. 2014 Nov 24;2014(11):CD001831. 10.1002/14651858.CD001831.pub5

15. Rimsza ME, Newberry S. Unexpected infant deaths associated with use of cough and cold medications. Pediatrics. 2008 Aug;122(2):e318–22. 10.1542/peds.2007-3813

16. Afssaps (2010) Mucolytiques, mucofluidifiants et Hélicidine : contre-indication chez l’enfant de moins de deux ans. https://www.lequotidiendupharmacien.fr/archives/mucolytiques-mucofluidifiants-et-helicidine-contre-indication-chez-lenfant-de-moins-de-deux-ans (accessed 1-04-2021)

17. AIFA. Nota Informativa Dell’agenzia Italiana Del Farmaco. Ufficio di Farmacovigilanza. Agenzia Italiana del Farmaco. 11-2010.

18. Manti S, Tosca MA, Licari A, Brambilla I, Foiadelli T, Ciprandi G, Marseglia GL. Cough Remedies for Children and Adolescents: Current and Future Perspectives. Paediatr Drugs. 2020 Dec;22(6):617-634. 10.1007/s40272-020-00420-4

19. Bones K, Mills S. Principles and practice of phytotherapy. 2nd ed. London: Churchill Livingstone Elsevier; 2013.

20. Gertsch J1. Botanical drugs, synergy, and network pharmacology: Forth and back to intelligent mixtures. Planta Med. 2011;77:1086–98. 10.1055/s-0030-1270904

21. Racchi M, Govoni S. The concept of non-pharmacological mechanism of action in medical devices made of substances in practice: What pharmacology can do to promote the scientific implementation of the European medical device regulation. Pharmadvances. 2020;01s:4–12. 10.36118/pharmadvances.01.2020.02s

22. Effert T, Koch E. Complex interactions between phyto-chemicals. The multi-target therapeutic concept of phyto-therapy. Current Drug Targets. 2011;12:122–32. 10.2174/138945011793591626

23. Barański M, Średnicka-Tober D, Volakakis N, Seal C, Sanderson R, Stewart G, et al. Higher antioxidant and lower cadmium concentrations and lower incidence of pesticide residues in organically grown crops: A systematic literature review and meta-analyses. Brit J Nutr. 2014;112:794–811. 10.1017/S0007114514001366

24. European Food Safety Authority (EFSA), Paula Medina-Pastor, Giuseppe Tacchini. The 2018 European Union report on pesticide residues in food. EFSA Journal 2020;18(4):6057. 10.2903/j.efsa.2020.6057

25. Mattoli L, Burico M, Fodaroni G, Tamimi S, Bedfont S, Traldi P, et al. New frontiers in pharmaceutical analysis: A metabolomic approach to check batch compliance of complex products based on natural substances. J Pharm Biomed Anal. 2016;126:156–62. 10.1016/j.jpba.2016.04.010

26. Murgia V, Manti S, Licari A, De Filippo M, Ciprandi G, Marseglia GL. Upper respiratory tract infection-associated acute cough and the urge to cough: New insights for clinical practice. Pediatr Allergy Immunol Pulmonol. 2020;33:3–11. 10.1089/ped.2019.1135

27. Hegland KW, Pitts T, Bolser DC, Davenport PW. Bratisl LL. Urge to cough with voluntary suppression following mechanical pharyngeal stimulation. 2011;112(3):109–14. PMid: 21452760

28. Eccles R, Dicpinigaitis P, Turner RB, Druce HM, Adeleke M, Mann AL. Characterization of urge to cough and cough symptoms associated with the common cold: Results of a US internet survey. Postgrad Med. 2016;128(5):485–91. 10.1080/00325481.2016.1185376

29. Smart JD. The basics and underlying mechanisms of muco-adhesion. Adv Drug Deliv Rev. 2005;57:1556–68. 10.1016/j.addr.2005.07.001

30. Thirawong N, Nunthanid J, Puttipipatkhachorn S, Sriamornsak P. Mucoadhesive properties of various pectins on gastrointestinal mucosa: An in vitro evaluation using texture analyzer. Eur J Pharm Biopharm. 2007;67:132–40. 10.1016/j.ejpb.2007.01.010

31. Avachat AM, Dash RR, Shrotriya SN. Recent investigations of plant-based natural gums, mucilages, and resins in novel drug delivery systems. Ind J Pharm Edu Res. 2011;45:1.

32. Schmidgall J. Evidence for bioadhesive effects of polysaccharides and polysaccharide-containing herbs in an ex vivo bioadhesion assay on buccal membranes. Planta Med. 2000;66:48–53. 10.1055/s-2000-11118

33. ESCOP European Scientific Cooperative On Phytotherapy. ESCOP monographs The Scientific Foundation for Herbal Medicinal Products. Althaea radix–Marshmallow root. Exeter: ESCOP; 2019. Online series. pp.1–2. https://escop.com/althaeae-radix-marshmallow-root-online-consultation/

34. Galati EM, Monforte MT, Miceli N. Opuntia ficus indica (L.) Mill. mucilages show cytoprotective effect on gastric mucosa in rats. Phytother Res. 2007;21(4):344–6. 10.1002/ptr.2075

35. Nosalova G, Fleskova D, Jurecek L. Herbal polysaccharides, and cough reflex. Respir Physiol Neurobiol. 2013;187:47–51. 10.1016/j.resp.2013.03.015

36. ESCOP Monographs. Myrrha. Online series, 2014. pp 1–2.

37. Sangiorgi E, Minelli E, Crescini G, Garzanti S. Fitoterapia. Casa Editrice Ambrosiana. Milan, Italy; 2007.

38. Schulz V, Hansel R, Blumenthal M, Tyler VE. Rational phytotherapy. A reference guide for physicians and pharmacists. 5th ed. Berlin: Springer-Verlag; 2004. 10.1007/978-3-662-09666-6

39. Tisserand R, Young R. Essential oil safety. 2nd ed. Edinburgh, UK: Churchill Livingstone Elsevier; 2014. 10.1016/B978-0-443-06241-4.00013-8

40. Tomás-Barberán FA, Truchado P, Ferreres F. Flavonoids in stingless-bee and honey-bee honeys. In: Pot-honey: A legacy of stingless bees. Editors Patricia Vit., Silvia R. M. Pedro, David Roubik. Chap. 33. Springer; New York 2013. pp. 461–74). 10.1007/978-1-4614-4960-7_33

41. Jibril FI, Hilmi ABM, Manivannan L. Isolation and characterization of polyphenols in natural honey for the treatment of human diseases. Bull Natl Res Cent. 2019;43:4. 10.1186/s42269-019-0044-7

42. Goldman RD. Honey for treatment of cough in children. Can Fam Physician. 2014;60:1107–8. PMid: 25642485

43. Cohen HA, Rozen J, Kristal H, Laks Y, Berkovitch M, Uziel Y, Kozer E, Pomeranz A, Efrat H. Effect of honey on nocturnal cough and sleep quality: a double-blind, randomized, placebo-controlled study. Pediatrics. 2012 Sep;130(3):465-71. 10.1542/peds.2011-3075

44. World Health Organization (WHO). Department of Child and Adolescent Health. Cough and cold remedies for the treatment of acute respiratory infections in young children. Geneva, Switzerland: World Health Organization; 2001. https://www.who.int/maternal_child_adolescent/documents/fch_cah_01_02/en/

45. Cianciosi D, Forbes-Hermandez TY, Afrin S, et al. Phenolic compounds in honey and their associated health benefits: A review. Molecules. 2018;23:2322. 10.3390/molecules23092322

46. Shadkam MN, Mozaffari-Khosravi H, Mozayan MR. A comparison of the effect of honey, dextromethorphan, and diphenhydramine on nightly cough and sleep quality in children and their parents. J Altern Complement Med. 2010;16:787–93. 10.1089/acm.2009.0311

47. Oduwole O, Udoh EE, Oyo-Ita A, et al. Honey for acute cough in children. Cochrane Database Syst Rev. 2018;CD007094. 10.1002/14651858.CD007094.pub5

48. Cohen HA, Rozen J, Kristal H, Laks Y, Berkovitch M, Uziel Y, et al. Effect of honey on nocturnal cough and sleep quality: A double-blind, randomized, placebo-controlled study. Pediatrics. 2012;130:465–71. 10.1542/peds.2011-3075

49. Murgia V, Manti S, Licari A, et al. Upper respiratory tract infection-associated acute cough and the urge to cough: New insights for clinical practice. Pediatr Allergy Immunol Pulmonol. 2020;33:3–13. 10.1089/ped.2019.1135

50. Malesker MA, Callahan-Lyon P, Ireland B, Irwin RS; CHEST Expert Cough Panel. Pharmacologic and nonpharmacologic treatment for acute cough associated with the common cold: CHEST Expert Panel Report. Chest. 2017;152:1021–37. 10.1016/j.chest.2017.08.009

51. Koepke R, Sobel J, Arnon SS. Global occurrence of infant botulism, 1976-2006. Pediatrics. 2008 Jul;122(1):e73-82. 10.1542/peds.2007-1827.

52. Cox N, Hinkle R. Infant botulism. Am Fam Physician. 2002;65:1388–92. PMid: 11996423.

53. Lee VS, Humphreys IM, Purcell PL, Davis GE. Manuka honey sinus irrigation for the treatment of chronic rhinosinusitis: A randomized controlled trial. Int Forum Allergy Rhinol. 2017;7:365–72. 10.1002/alr.21898

54. Canciani M, Murgia V, Caimmi D, Anapurapu S, Licari A, Marseglia GL. Efficacy of Grintuss® pediatric syrup in treating cough in children: A randomized, multicenter, double-blind, placebo-controlled clinical trial. Ital J Pediatr. 2014;40:56. 10.1186/1824-7288-40-56

55. Cohen HA, Hoshen M, Gur S, Bahir A, Laks Y, Blau H. Efficacy and tolerability of a polysaccharide-resin-honey based cough syrup as compared to carbocysteine syrup for children with colds: A randomized, single-blinded, multicenter study. World J Pediatr 2017;13:27–33. 10.1007/s12519-016-0048-4

56. National Library of Medicine (US). Drugs and lactation database (LactMed). [Internet]. National Library of Medicine (US), Bethesda, MD; 2006. Marshmallow. (Last Revision: February 15, 2021.). https://www.ncbi.nlm.nih.gov/books/NBK501839/ (accessed 1-04-2021)

57. Grujičić D, Stošić I, Kosanić M, et al. Evaluation of in vitro antioxidant, antimicrobial, genotoxic and anticancer activities of lichen Cetraria islandica. Cytotechnology. 2014;66:803–13. 10.1007/s10616-013-9629-4

58. PDR for Herbal Medicines. 2000. Scientific Editors: Gruenwald J, Brendler T, Jaenicke C. Thomson. Medical Economics Company, Inc. a Montvale NY. 4th Edition. Available from: https://www.academia.edu/42179490/PDR_for_Herbal_Medicines_4th_Edition (accessed 1-04-2021)

59. ESCOP Monographs. Lichen islandicus. 2nd ed. Thieme; Exeter UK. 2003, pp. 286–289.

60. European Scientific Cooperative On Phytotherapy. ESCOP monographs The Scientific Foundation for Herbal Medicinal Products. Online series. Malvae flos (Mallow Flower). Exeter: ESCOP; 2016. pp. 1–2. https://escop.com/malvae-flos-mallow-flower-online-consultation/ (accessed 1-04-2021)

61. Gasparetto JC, Martins CA, Hayashi SS, Otuky MF, Pontarolo R. Ethnobotanical and scientific aspects of Malva sylvestris L.: A millennial herbal medicine. J Pharm Pharmacol. 2012;64:172–89. 10.1111/j.2042-7158.2011.01383.x

62. European Scientific Cooperative On Phytotherapy. ESCOP monographs The Scientific Foundation for Herbal Medicinal Products. Online series. Plantaginis lanceolatae folium/ herba (Ribwort plantain leaf/herb). Exeter: ESCOP; 2013. p. 1. https://escop.com/plantaginis-lanceolatae-folium-herba-ribwort-plantain-leaf-herb-online-consultation/ (accessed 1-04-2021)

63. European Scientific Cooperative On Phytotherapy. ESCOP monographs The Scientific Foundation for Herbal Medicinal Products. Online series. Grindeliae herba (Grindelia) Exeter: ESCOP; 2015, p. 1. https://escop.com/downloads/grindelia/ (accessed 1-04-2021)

64. Zerbe P, Rodriguez SM, Mafu S, Chiang A, Sandhu HK, O’Neil-Johnson M. Exploring diterpene metabolism in non-model species: Transcriptome-enabled discovery and functional characterization of lambda-7,13E-dienyl diphosphate synthase from grindelia robusta. Plant J. 2015;83:783–93. 10.1111/tpj.12925

65. ESCOP Monographs. Hederae helicis folium. 2nd ed. Thieme; Exeter UK. 2003, pp. 241–7.

66. ESCOP Monographs. Primulae radix. 2nd ed. Thieme; Exeter UK. 2003, pp. 407–10.

67. Golden H, Ozgen U, Atila A, Ozturk H, Kazaz C, Duman H. Phytochemical studies and quantitative HPLC analysis of rosmarinic acid and luteolin 5-O-β-D-glucopyranoside on thymus praecox subsp. grossheimii var. grossheimii. Chem Pharm Bull (Tokyo). 2015;63:720–5. 10.1248/cpb.c14-00877

68. Fatma G, Farhat Mouna B, Mother M, Ahmed L. In-vitro assessment of antioxidant and antimicrobial activities of methanol extracts and essential oil of thymus hirtus sp. algeriensis. Lipids Health Dis. 2014;13:114. 10.1186/1476-511X-13-114

69. Beer AM, Loew D. Medicinal plants for infections of the upper and lower respiratory tract: Practical recommendations. MMW Fortschr Med. 2008;150:29–33. PMid: 19013839.

70. Kemmerich B, Eberhardt R, Stammer H. Efficacy and tolerability of a fluid extract combination of thyme herb and ivy leaves and matched placebo in adults suffering from acute bronchitis with productive cough. A prospective, double-blind, placebo-controlled clinical trial. Arzneimittelforschung. 2006;56:652–60. 10.1055/s-0031-1296767

71. Kemmerich B. Evaluation of efficacy and tolerability of a fixed combination of dry extracts of thyme herb and primrose root in adults suffering from acute bronchitis with productive cough. A prospective, double-blind, placebo-controlled multicentre clinical trial. Arzneimittelforschung. 2007;57:607–15. 10.1055/s-0031-1296656

72. ESCOP Monographs. Thymi herba. 2nd ed. Thieme; Exeter UK. 2003, pp. 607–14.

73. ESCOP Monographs. Menthae piperitae aetheroleum. 2nd ed. Thieme; Exeter UK. 2003, pp. 329–36.

74. Flaman Z, Pellechia-Clarke S, Bailey B, McGuigan M. Unintentional exposure of young children to camphor and eucalyptus oils. Paediatr Child Health. 2001;6(2):80–3. 10.1093/pch/6.2.80

75. Fraternal D, Flamini G, Ascrizzi R. In Vitro anticollagenase and antielastase activities of essential oil. of helichrysum italicum subsp. italicum (Roth) G. Don. J Med Food 2019;22:1041–6. 10.1089/jmf.2019.0054

76. Viegas DA, Plameira-de-Oliveira A, Salgueiro L, Martinez-de-Oliveira J, Palmeira-de-Oliveira R. Helichrysum italicum: From traditional use to scientific data. J Ethnopharmacol. 2014;151:54–65. 10.1016/j.jep.2013.11.005

77. Timmer A, Günther J, Motschall E, Rücker G, Antes G, Kern WV. Pelargonium sidoides extract for treating acute respiratory tract infections. Cochrane Database Syst Rev. 2013;10:CD006323. 10.1002/14651858.CD006323.pub3

78. Kamin W, Maydannik VG, Malek FA, Kieser M. Efficacy and tolerability of EPs 7630 in patients (aged 6--18 years old) with acute bronchitis. Acta Paediatrica. 2010;99:537–43. 10.1111/j.1651-2227.2009.01656.x

79. Martin D, Konrad M, Adarkwah CC, Kostov K. Reduced antibiotic use after initial treatment of acute respiratory infections with phytopharmaceuticals–A retrospective cohort study. Postgrad Med. 2020;20:1–7. 10.1080/00325481.2020.1751497

80. European Scientific Cooperative On Phytotherapy. ESCOP monographs The Scientific Foundation for Herbal Medicinal Products. Online series. Pelargonii radix (Pelargonium root). Exeter: ESCOP; 2015.p. 1. (accessed 1-04-2021)

81. Holmes S, Valentin R, Marechal P, Mouloungui Z. Esters of oligo-(glycerol carbonate-glycerol): New biobased oligomeric surfactants. J Colloid Interface Sci. 2017;487:418–25. 10.1016/j.jcis.2016.10.072

82. European Food Safety Authority (EFSA) Panel on Food Additives and Nutrient Sources added to Food (ANS). Re-evaluation of glycerol (E 422) as a food additive; EFSA Journal 2017;15(3):4720 p. 13. Available from: https://efsa.onlinelibrary.wiley.com/doi/full/10.2903/j.efsa.2017.4720 (accessed 01-04-2021)

83. Eccles R. The powerful placebo in cough studies. Pulm Pharmacol Ther. 2002;15:303–8. 10.1006/pupt.2002.0364

84. Eccles R, Mallefet P. Soothing properties of glycerol in cough syrups for acute cough due to common cold. Pharmacy (Basel). 2017;5(1):4. 10.3390/pharmacy5010004

85. Shrivastava R, Carrois F, Pisak M, Chabrillat T, Shrivastava R. Clinical efficacy of novel filmogen, antimicrobial, cleaning, fluidizing cough treatment. J Clin Trials. 2017;7:318. 10.4172/2167-0870.1000318

86. World Health Organization (WHO). Cough and cold remedies for the treatment of acute respiratory infections in young children. Pamphlet WHO/FCH/CAH/01.02. Geneva, Switzerland: WHO; 2001. https://www.who.int/maternal_child_adolescent/documents/fch_cah_01_02/en/

87. Kamatou GP, Vermaak I, Viljoen AM, Lawrence BM. Menthol: A simple monoterpene with remarkable biological properties. Phytochemistry. 2013;96:15–25. 10.1016/j.phytochem.2013.08.005

88. Morice AH. Over-the-counter cough medicines: New approaches. Pulm Pharmacol Ther. 2015 Dec;35:149-51. 10.1016/j.pupt.2015.07.006

89. Smith AP, Boden C. Effects of chewing menthol gum on the alertness of healthy volunteers and those with an upper respiratory tract illness. Stress Health. 2011;29:138–42. 10.1002/smi.2437

90. Gillissen A, Wittig T, Ehmen M, Krezdorn HG, de Mey C. A multi-centre, randomized, double-blind, placebo-controlled clinical trial on the efficacy and tolerability of GeloMyrtol® forte in acute bronchitis. Drug Res (Stuttg). 2013;63:19–27. 10.1055/s-0032-1331182

91. Birring SS, Brew J, Kilbourn A, Edwards V, Wilson R, Morice AH. Rococo study: A real-world evaluation of an over-the-counter medicine in acute cough (a multicentre, randomized, controlled study). BMJ Open. 2017;7:e014112. 10.1136/bmjopen-2016-014112

92. Johnson D, Mead R, Kennelty K, Hahn D. Menthol cough drops: Cause for concern? J Am Board Fam Med. 2018;31:183–91. 10.3122/jabfm.2018.02.170363

93. Tisserand R, Young R. Essential oil safety. 2nd ed. Edinburgh, UK: Churchill Livingstone Elsevier; 2014, 108 p. 10.1016/B978-0-443-06241-4.00013-8

94. Caceres AI, Liu B, Jabba SV, Achanta S, Morris JB, Jordt SE. Transient receptor potential cation channel subfamily M member 8 channels mediate the anti-inflammatory effects of eucalyptol. Br J Pharmacol. 2017;174: 867–79. 10.1111/bph.13760

95. Yu N, Sun Yt, Su XM, He M, Dai B, Kang J. Treatment with eucalyptol mitigates cigarette smoke-induced lung injury through suppressing ICAM-1 gene expression. Biosci Rep. 2018;38:BSR20171636. 10.1042/BSR20171636

96. Tisserand R, Young R. Essential oil safety. 2nd ed. Edinburgh, UK: Churchill Livingstone Elsevier; 2014, 273 p. 10.1016/B978-0-443-06241-4.00013-8

97. Marchese A, Orhan IE, Daglia M, Barbieri R, Di Lorenzo A, Nabavi SF, et al. Antibacterial and antifungal activities of thymol: A brief review of the literature. Food Chem. 2016; 210:402–14. 10.1016/j.foodchem.2016.04.111

98. Schonknecht K, Krauss H, Jambor J, Fal AM. Treatment of cough in respiratory tract infections–The effect of combining the natural active compounds with thymol. Wild Lek. 2016;69:791–8. PMid: 28214817.

99. Briars LA. The latest update on over-the-counter cough and cold product use in children. J Pediatr Pharmacol Ther. 2009 Jul;14(3):127–31. doi:10.5863/1551-6776-14.3.127. PMid: 23055900; PMCID: PMC3461939.

100. Interpress Service News Agency. COUGH REMEDIES MARKET SIZE FORECAST TO REACH $1.45 BILLION BY 2025. JULY 15, 2020 Available from: http://ipsnews.net/business/2020/07/15/cough-remedies-market-size-forecast-to-reach-1-45-billion-by-2025/) (accessed 01-04-2021)

101. European MedicinesAgency (EMA). Committee on Herbal Medicinal Products (HMPC). Reflection paper on ethanol content in herbal medicinal products and traditional herbal medicinal products used in children. Del 14-Gennaio; 2010 (Doc 1). Available from: https://www.ema.europa.eu/en/ethanol-content-herbal-medicinal-products-traditional-herbal-medicinal-products-used-children#current-version-section (accessed 1-04-2021)

102. European MedicinesAgency (EMA). Committee for Human Medicinal Products (CHMP). Questions and answers on ethanol in the context of the revision of the guideline on ‘excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00) Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-ethanol-context-revision-guideline-excipients-label-package-leaflet-medicinal_en.pdf

103. Jeschke, E., Ostermann, T., Lüke, C. et al. Remedies containing asteraceae extracts. Drug Safety. 2009;32:691–706. 10.2165/00002018-200932080-00007