Efficacy of Oral Mucoadhesive N-acetylcysteine Tablets in Treatment of Recurrent Aphthous Stomatitis: A Randomized Double-Blind, Placebo-Controlled Clinical Trial
Aphthous Stomatitis Therapy with N-acetylcysteine
,
Abstract
Objectives: This study aimed to assess the efficacy of oral mucoadhesive N-acetylcysteine (NAC) tablets for treatment of recurrent aphthous stomatitis (RAS).
Materials and Methods: Forty-nine patients with RAS were randomized to receive mucoadhesive NAC tablets (n=25) or placebo (n=24). Tablets were prescribed three times a day for 7 days in each group. Pain intensity was evaluated with visual analog scale (VAS) three times a day from day 1 to day 7. Also, patients were clinically examined on days 0 (before entering the study), 3, 5, and 7 using a metal caliper to measure the diameter of the lesions. The data were statistically analyzed and P<0.05 was considered statistically significant.
Results: Regarding the VAS score, all participants in the treatment group showed complete recovery on day 7 (P<0.01). Also, the diameter of the lesions was significantly smaller in the treatment group than the placebo group at the end of the study (P<0.001).
Conclusion: The results of this clinical trial showed for the first time that mucoadhesive NAC tablets can significantly decrease pain and the diameter of RAS lesions without any systemic complications.
1. Ciçek Y, Canakçi V, Ozgöz M, Ertas U, Canakçi E. Prevalence and handedness correlates of recurrent aphthous stomatitis in the Turkish population. J Public Health Dent. 2004 Summer;64(3):151-6.
2. Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2014 Apr;58(2):281-97.
3. Tarakji B, Gazal G, Al-Maweri SA, Azzeghaiby SN, Alaizari N. Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental practitioners. J Int Oral Health. 2015 May;7(5):74-80.
4. Al-Omiri MK, Karasneh J, Alhijawi MM, Zwiri AM, Scully C, Lynch E. Recurrent aphthous stomatitis (RAS): a preliminary within-subject study of quality of life, oral health impacts and personality profiles. J Oral Pathol Med. 2015 Apr;44(4):278-83.
5. Hapa A, Aksoy B, Polat M, Aslan U, Atakan N. Does recurrent aphthous stomatitis affect quality of life? A prospective study with 128 patients evaluating different treatment modalities. J Dermatolog Treat. 2011 Aug;22(4):215-20.
6. Krisdapong S, Sheiham A, Tsakos G. Impacts of recurrent aphthous stomatitis on quality of life of 12- and 15-year-old Thai children. Qual Life Res. 2012 Feb;21(1):71-6.
7. McCullough MJ, Abdel-Hafeth S, Scully C. Recurrent aphthous stomatitis revisited; clinical features, associations, and new association with infant feeding practices? J Oral Pathol Med. 2007 Nov;36(10):615-20.
8. Sun A, Chen HM, Cheng SJ, Wang YP, Chang JY, Wu YC, et al. Significant association of deficiencies of hemoglobin, iron, vitamin B12, and folic acid and high homocysteine level with recurrent aphthous stomatitis. J Oral Pathol Med. 2015 Apr;44(4):300-5.
9. Babaei Hatkehlouei M, Dadgar S, Shokrzadeh M, Mousavi J, Sobouti F. A Review of the Requirements and Hazards of Toxic Metals From Orthodontic Wires. Pharm Biomed Res 2020; 6 (4) :251-260
10. Akoglu G, Metin A, Kilinc F, Pektas SD, Isikoglu S, Akbas A, et al. Total serum oxidant/antioxidant status and arylesterase activity in recurrent aphthous stomatitis. Ann Dermatol. 2013 Aug;25(3):273-7.
11. Bagan J, Saez G, Tormos C, Gavalda C, Sanchis JM, Bagan L, et al. Oxidative stress and recurrent aphthous stomatitis. Clin Oral Investig. 2014 Nov;18(8):1919-23.
12. Bilgili SG, Ozkol H, Takci Z, Ozkol HU, Karadag AS, Aslan M. Assessment of the serum paraoxonase activity and oxidant/antioxidant status in patients with recurrent aphthous stomatitis. Int J Dermatol. 2013 Oct;52(10):1259-64.
13. Tugrul S, Koçyiğit A, Doğan R, Eren SB, Senturk E, Ozturan O, et al. Total antioxidant status and oxidative stress in recurrent aphthous stomatitis. Int J Dermatol. 2016 Mar;55(3):e130-5.
14. Sawair FA. Does smoking really protect from recurrent aphthous stomatitis? Ther Clin Risk Manag. 2010 Nov 22;6:573-7.
15. Hamedi S, Sadeghpour O, Shamsardekani MR, Amin G, Hajighasemali D, Feyzabadi Z. The Most Common Herbs to Cure the Most Common Oral Disease: Stomatitis Recurrent Aphthous Ulcer (RAU). Iran Red Crescent Med J. 2016 Feb 13;18(2):e21694.
16. Abdulrab S, Halboub E, Barngkgei I, Al-Hebshi N. N-acetylcysteine as a candidate therapeutic for recurrent aphthous and aphthous-like ulcers. Dent Hypotheses. 2017 Jan 1;8(1):17.
17. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014 Feb;141(2):150-9.
18. Bémeur C, Vaquero J, Desjardins P, Butterworth RF. N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis. 2010 Jun;25(2):241-9.
19. Sansone RA, Sansone LA. Getting a Knack for NAC: N-Acetyl-Cysteine. Innov Clin Neurosci. 2011 Jan;8(1):10-4.
20. Heard K, Rumack BH, Green JL, Bucher-Bartelson B, Heard S, Bronstein AC, et al. A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning. Clin Toxicol (Phila). 2014 Jun;52(5):512-8.
21. Cağlayan F, Miloglu O, Altun O, Erel O, Yilmaz AB. Oxidative stress and myeloperoxidase levels in saliva of patients with recurrent aphthous stomatitis. Oral Dis. 2008 Nov;14(8):700-4.
22. Albanidou-Farmaki E, Markopoulos AK, Kalogerakou F, Antoniades DZ. Detection, enumeration and characterization of T helper cells secreting type 1 and type 2 cytokines in patients with recurrent aphthous stomatitis. Tohoku J Exp Med. 2007 Jun;212(2):101-5.
23. Dalghous AM, Freysdottir J, Fortune F. Expression of cytokines, chemokines, and chemokine receptors in oral ulcers of patients with Behcet's disease (BD) and recurrent aphthous stomatitis is Th1-associated, although Th2-association is also observed in patients with BD. Scand J Rheumatol. 2006 Nov-Dec;35(6):472-5.
24. Freysdottir J, Lau S, Fortune F. Gammadelta T cells in Behçet's disease (BD) and recurrent aphthous stomatitis (RAS). Clin Exp Immunol. 1999 Dec;118(3):451-7.
25. Ozyurt K, Celik A, Sayarlıoglu M, Colgecen E, Incı R, Karakas T, et al. Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis. J Oral Pathol Med. 2014 Oct;43(9):691-5.
26. Tsai ML, Huang HP, Hsu JD, Lai YR, Hsiao YP, Lu FJ, et al. Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC/Stat3 pathway. Int J Mol Sci. 2014 May 2;15(5):7563-78.
27. Halboub E, Alkadasi B, Alakhali M, AlKhairat A, Mdabesh H, Alkahsah S, et al. N-acetylcysteine versus chlorhexidine in treatment of aphthous ulcers: a preliminary clinical trial. J Dermatolog Treat. 2021 Sep;32(6):649-653.
28. Babaee N, Zabihi E, Mohseni S, Moghadamnia AA. Evaluation of the therapeutic effects of Aloe vera gel on minor recurrent aphthous stomatitis. Dent Res J (Isfahan). 2012 Jul;9(4):381-5.
29. Glick M. Burket's oral medicine. PMPH USA; 2015.
30. Slebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review. Arch Immunol Ther Exp (Warsz). 2014 Jun;62(3):205-15. doi: 10.1007/s00005-013-0261-y. Epub 2013 Nov 12.
31. Deshmukh VN, Jadhav JK, Sakarkar DM. Formulation and in vitro evaluation of theophylline anhydrous bioadhesive tablets. Asian J Pharm. 2009;3:54–8.
32. Kiraz S, Akdogan A, Karadag O, Erden AB, Kilic L, Kalyoncu U, et al. AB1173 Prevalence of Recurrent Aphthous Stomatitis and Related Factors: Outcomes of Cappadocia Chronic Diseases Epidemiological Study. Annals of the Rheumatic Diseases 2015;74:1295.
33. Dixit V, Dixit M, Hegde V, Sathe S, Jadhav S. Clinical evaluation of conventional and laser tooth preparation using visual analogue scale. J Dent Lasers. 2013 Jan 1;7(1):27.
34. Pedersen A. Psychologic stress and recurrent aphthous ulceration. J Oral Pathol Med. 1989 Feb;18(2):119-22.
35. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc. 2003 Feb;134(2):200-7.
36. Saral Y, Coskun BK, Ozturk P, Karatas F, Ayar A. Assessment of salivary and serum antioxidant vitamins and lipid peroxidation in patients with recurrent aphthous ulceration. Tohoku J Exp Med. 2005 Aug;206(4):305-12.
37. Momen-Beitollahi J, Mansourian A, Momen-Heravi F, Amanlou M, Obradov S, Sahebjamee M. Assessment of salivary and serum antioxidant status in patients with recurrent aphthous stomatitis. Med Oral Patol Oral Cir Bucal. 2010 Jul 1;15(4):e557-61.
38. Kuyumcu A, Akyol A, Buyuktuncer Z, Ozmen MM, Besler HT. Improved oxidative status in major abdominal surgery patients after N-acetyl cystein supplementation. Nutr J. 2015 Jan 6;14:4.
39. Mao G, Goswami M, Kalen AL, Goswami PC, Sarsour EH. N-acetyl-L-cysteine increases MnSOD activity and enhances the recruitment of quiescent human fibroblasts to the proliferation cycle during wound healing. Mol Biol Rep. 2016 Jan;43(1):31-9.
40. Li CL, Huang HL, Wang WC, Hua H. Efficacy and safety of topical herbal medicine treatment on recurrent aphthous stomatitis: a systemic review. Drug Des Devel Ther. 2015 Dec 31;10:107-15.
2. Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2014 Apr;58(2):281-97.
3. Tarakji B, Gazal G, Al-Maweri SA, Azzeghaiby SN, Alaizari N. Guideline for the diagnosis and treatment of recurrent aphthous stomatitis for dental practitioners. J Int Oral Health. 2015 May;7(5):74-80.
4. Al-Omiri MK, Karasneh J, Alhijawi MM, Zwiri AM, Scully C, Lynch E. Recurrent aphthous stomatitis (RAS): a preliminary within-subject study of quality of life, oral health impacts and personality profiles. J Oral Pathol Med. 2015 Apr;44(4):278-83.
5. Hapa A, Aksoy B, Polat M, Aslan U, Atakan N. Does recurrent aphthous stomatitis affect quality of life? A prospective study with 128 patients evaluating different treatment modalities. J Dermatolog Treat. 2011 Aug;22(4):215-20.
6. Krisdapong S, Sheiham A, Tsakos G. Impacts of recurrent aphthous stomatitis on quality of life of 12- and 15-year-old Thai children. Qual Life Res. 2012 Feb;21(1):71-6.
7. McCullough MJ, Abdel-Hafeth S, Scully C. Recurrent aphthous stomatitis revisited; clinical features, associations, and new association with infant feeding practices? J Oral Pathol Med. 2007 Nov;36(10):615-20.
8. Sun A, Chen HM, Cheng SJ, Wang YP, Chang JY, Wu YC, et al. Significant association of deficiencies of hemoglobin, iron, vitamin B12, and folic acid and high homocysteine level with recurrent aphthous stomatitis. J Oral Pathol Med. 2015 Apr;44(4):300-5.
9. Babaei Hatkehlouei M, Dadgar S, Shokrzadeh M, Mousavi J, Sobouti F. A Review of the Requirements and Hazards of Toxic Metals From Orthodontic Wires. Pharm Biomed Res 2020; 6 (4) :251-260
10. Akoglu G, Metin A, Kilinc F, Pektas SD, Isikoglu S, Akbas A, et al. Total serum oxidant/antioxidant status and arylesterase activity in recurrent aphthous stomatitis. Ann Dermatol. 2013 Aug;25(3):273-7.
11. Bagan J, Saez G, Tormos C, Gavalda C, Sanchis JM, Bagan L, et al. Oxidative stress and recurrent aphthous stomatitis. Clin Oral Investig. 2014 Nov;18(8):1919-23.
12. Bilgili SG, Ozkol H, Takci Z, Ozkol HU, Karadag AS, Aslan M. Assessment of the serum paraoxonase activity and oxidant/antioxidant status in patients with recurrent aphthous stomatitis. Int J Dermatol. 2013 Oct;52(10):1259-64.
13. Tugrul S, Koçyiğit A, Doğan R, Eren SB, Senturk E, Ozturan O, et al. Total antioxidant status and oxidative stress in recurrent aphthous stomatitis. Int J Dermatol. 2016 Mar;55(3):e130-5.
14. Sawair FA. Does smoking really protect from recurrent aphthous stomatitis? Ther Clin Risk Manag. 2010 Nov 22;6:573-7.
15. Hamedi S, Sadeghpour O, Shamsardekani MR, Amin G, Hajighasemali D, Feyzabadi Z. The Most Common Herbs to Cure the Most Common Oral Disease: Stomatitis Recurrent Aphthous Ulcer (RAU). Iran Red Crescent Med J. 2016 Feb 13;18(2):e21694.
16. Abdulrab S, Halboub E, Barngkgei I, Al-Hebshi N. N-acetylcysteine as a candidate therapeutic for recurrent aphthous and aphthous-like ulcers. Dent Hypotheses. 2017 Jan 1;8(1):17.
17. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014 Feb;141(2):150-9.
18. Bémeur C, Vaquero J, Desjardins P, Butterworth RF. N-acetylcysteine attenuates cerebral complications of non-acetaminophen-induced acute liver failure in mice: antioxidant and anti-inflammatory mechanisms. Metab Brain Dis. 2010 Jun;25(2):241-9.
19. Sansone RA, Sansone LA. Getting a Knack for NAC: N-Acetyl-Cysteine. Innov Clin Neurosci. 2011 Jan;8(1):10-4.
20. Heard K, Rumack BH, Green JL, Bucher-Bartelson B, Heard S, Bronstein AC, et al. A single-arm clinical trial of a 48-hour intravenous N-acetylcysteine protocol for treatment of acetaminophen poisoning. Clin Toxicol (Phila). 2014 Jun;52(5):512-8.
21. Cağlayan F, Miloglu O, Altun O, Erel O, Yilmaz AB. Oxidative stress and myeloperoxidase levels in saliva of patients with recurrent aphthous stomatitis. Oral Dis. 2008 Nov;14(8):700-4.
22. Albanidou-Farmaki E, Markopoulos AK, Kalogerakou F, Antoniades DZ. Detection, enumeration and characterization of T helper cells secreting type 1 and type 2 cytokines in patients with recurrent aphthous stomatitis. Tohoku J Exp Med. 2007 Jun;212(2):101-5.
23. Dalghous AM, Freysdottir J, Fortune F. Expression of cytokines, chemokines, and chemokine receptors in oral ulcers of patients with Behcet's disease (BD) and recurrent aphthous stomatitis is Th1-associated, although Th2-association is also observed in patients with BD. Scand J Rheumatol. 2006 Nov-Dec;35(6):472-5.
24. Freysdottir J, Lau S, Fortune F. Gammadelta T cells in Behçet's disease (BD) and recurrent aphthous stomatitis (RAS). Clin Exp Immunol. 1999 Dec;118(3):451-7.
25. Ozyurt K, Celik A, Sayarlıoglu M, Colgecen E, Incı R, Karakas T, et al. Serum Th1, Th2 and Th17 cytokine profiles and alpha-enolase levels in recurrent aphthous stomatitis. J Oral Pathol Med. 2014 Oct;43(9):691-5.
26. Tsai ML, Huang HP, Hsu JD, Lai YR, Hsiao YP, Lu FJ, et al. Topical N-acetylcysteine accelerates wound healing in vitro and in vivo via the PKC/Stat3 pathway. Int J Mol Sci. 2014 May 2;15(5):7563-78.
27. Halboub E, Alkadasi B, Alakhali M, AlKhairat A, Mdabesh H, Alkahsah S, et al. N-acetylcysteine versus chlorhexidine in treatment of aphthous ulcers: a preliminary clinical trial. J Dermatolog Treat. 2021 Sep;32(6):649-653.
28. Babaee N, Zabihi E, Mohseni S, Moghadamnia AA. Evaluation of the therapeutic effects of Aloe vera gel on minor recurrent aphthous stomatitis. Dent Res J (Isfahan). 2012 Jul;9(4):381-5.
29. Glick M. Burket's oral medicine. PMPH USA; 2015.
30. Slebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review. Arch Immunol Ther Exp (Warsz). 2014 Jun;62(3):205-15. doi: 10.1007/s00005-013-0261-y. Epub 2013 Nov 12.
31. Deshmukh VN, Jadhav JK, Sakarkar DM. Formulation and in vitro evaluation of theophylline anhydrous bioadhesive tablets. Asian J Pharm. 2009;3:54–8.
32. Kiraz S, Akdogan A, Karadag O, Erden AB, Kilic L, Kalyoncu U, et al. AB1173 Prevalence of Recurrent Aphthous Stomatitis and Related Factors: Outcomes of Cappadocia Chronic Diseases Epidemiological Study. Annals of the Rheumatic Diseases 2015;74:1295.
33. Dixit V, Dixit M, Hegde V, Sathe S, Jadhav S. Clinical evaluation of conventional and laser tooth preparation using visual analogue scale. J Dent Lasers. 2013 Jan 1;7(1):27.
34. Pedersen A. Psychologic stress and recurrent aphthous ulceration. J Oral Pathol Med. 1989 Feb;18(2):119-22.
35. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: a consensus approach. J Am Dent Assoc. 2003 Feb;134(2):200-7.
36. Saral Y, Coskun BK, Ozturk P, Karatas F, Ayar A. Assessment of salivary and serum antioxidant vitamins and lipid peroxidation in patients with recurrent aphthous ulceration. Tohoku J Exp Med. 2005 Aug;206(4):305-12.
37. Momen-Beitollahi J, Mansourian A, Momen-Heravi F, Amanlou M, Obradov S, Sahebjamee M. Assessment of salivary and serum antioxidant status in patients with recurrent aphthous stomatitis. Med Oral Patol Oral Cir Bucal. 2010 Jul 1;15(4):e557-61.
38. Kuyumcu A, Akyol A, Buyuktuncer Z, Ozmen MM, Besler HT. Improved oxidative status in major abdominal surgery patients after N-acetyl cystein supplementation. Nutr J. 2015 Jan 6;14:4.
39. Mao G, Goswami M, Kalen AL, Goswami PC, Sarsour EH. N-acetyl-L-cysteine increases MnSOD activity and enhances the recruitment of quiescent human fibroblasts to the proliferation cycle during wound healing. Mol Biol Rep. 2016 Jan;43(1):31-9.
40. Li CL, Huang HL, Wang WC, Hua H. Efficacy and safety of topical herbal medicine treatment on recurrent aphthous stomatitis: a systemic review. Drug Des Devel Ther. 2015 Dec 31;10:107-15.
| Issue | Vol 20 (Continuously Published Article-Based) | |
| Section | Original Article | |
| DOI | https://doi.org/10.18502/fid.v20i18.12824 | |
| Keywords | ||
| Acetylcysteine Stomatitis, Aphthous Visual Analog Scale | ||
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How to Cite
1.
Eslami G, Ghorbani A, Akbari J, Farmoudeh A, Faghih F, Moghimi M. Efficacy of Oral Mucoadhesive N-acetylcysteine Tablets in Treatment of Recurrent Aphthous Stomatitis: A Randomized Double-Blind, Placebo-Controlled Clinical Trial. Front Dent. 2023;20.
