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Safety and tolerability of cinnamaldehyde in orabase for oral candidiasis treatment: phase I clinical trial

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Abstract

Objective

To advance studies on the effect of a new pharmaceutical formulation for the treatment of oral fungal infections, we evaluated the safety and tolerability of orabase ointment containing cinnamaldehyde for use on the oral mucosa.

Material and methods

A clinical trial (phase I) was carried out on 35 individuals with healthy oral mucosa divided into three groups: ointments at 200 µg/mL, n = 12; 300 µg/mL, n = 11; and 400 µg/mL, n = 12. Product safety was assessed using three parameters: (a) clinical evolution as recorded by trained examiners; (b) evolution of the inflammatory process as registered by an exfoliative cytology exam and analyzed by trained pathologists; (c) mucosal swab to count Candida spp. colony-forming units (CFU). These parameters were analyzed both beforehand and at 15 days of treatment.

Results

The three ointment concentrations evaluated did not trigger inflammatory processes. The mycological analyses revealed a reduction of at least 99% in the number of Candida spp. CFU. In the exfoliative cytology analyses, the cells were found to be healthy. Participants reported a pleasant taste, yet 17% reported a slight burning sensation when applying the product.

Conclusions

The ointment is safe and tolerable for use on healthy oral mucosa.

Trial registration

Registration number: RBR-7zwzs3.

Clinical relevance

The ointment proved to be safe and tolerable for use on oral mucosa, encouraging studies to evaluate its clinical efficacy in patients with oral candidiasis, and contributing to a new therapeutic proposal for the treatment of fungal infections caused by Candida spp.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on request.

References

  1. Serrano J, López-Pintor RM, Ramírez L, Fernández-Castro M, Sanz M, Melchor S, Peiteado D, Hernández G (2020) Risk factors related to oral candidiasis in patients with primary Sjögren’s syndrome. Med Oral Patol Oral Cir Bucal 25:e700–e700. https://doi.org/10.4317/medoral.23719

    Article  PubMed  PubMed Central  Google Scholar 

  2. Telles DR, Karki N, Marshall MW (2017) Oral fungal infections: diagnosis and management. Dent Clin North Am 61:319–349. https://doi.org/10.1016/j.cden.2016.12.004

    Article  PubMed  Google Scholar 

  3. Mun MSS, Yap T, Alnuaimi AD, Adams GG, McCullough MJ (2016) Oral candidal carriage in asymptomatic patients. Aust Dent J 61:190–195. https://doi.org/10.1111/adj.12335

    Article  PubMed  Google Scholar 

  4. Shirazi JH, Ali MI, Alghamdi HA, Faryal R, Akhtar Z, Jamal A and Rashid A (2019) Pediatric oropharyngeal candidiasis: a comprehensive study on risk factors and most prevalent species of Candida. Pak J Pharm Sci 32.

  5. Bianchi CMPdC, Bianchi HA, Tadano T, Paula CRd, Hoffmann-Santos HD, Leite Jr DP and Hahn RC (2016) Factors related to oral candidiasis in elderly users and non-users of removable dental prostheses. Rev Inst Med Trop Sao Paulo 58. https://doi.org/10.1590/S1678-9946201658017

  6. Alrayyes SF, Alruwaili HM, Taher IA, Elrahawy KM, Almaeen AH, Ashekhi AO, Alam MK (2019) Oral Candidal carriage and associated risk indicators among adults in Sakaka, Saudi Arabia. BMC Oral Health 19:86–86. https://doi.org/10.1186/s12903-019-0775-8

    Article  PubMed  PubMed Central  Google Scholar 

  7. Martori E, Ayuso-Montero R, Willaert E, Viñas M, Peraire M, Martinez-Gomis J (2017) Status of removable dentures and relationship with oral Candida-associated factors in a geriatric population in Catalonia. J Prosthodont 26:370–375. https://doi.org/10.1111/jopr.12551

    Article  PubMed  Google Scholar 

  8. Millsop JW, Fazel N (2016) Oral candidiasis. Clin Dermatol 34:487–494. https://doi.org/10.1016/j.clindermatol.2016.02.022

    Article  PubMed  Google Scholar 

  9. Loster JE, Wieczorek A, Loster BW (2016) Correlation between age and gender in Candida species infections of complete denture wearers: a retrospective analysis. Clin Interv Aging 11:1707–1707. https://doi.org/10.2147/CIA.S116658

    Article  PubMed  PubMed Central  Google Scholar 

  10. Uludamar A, Özkan YK, Kadir T, Ceyhan I (2010) In vivo efficacy of alkaline peroxide tablets and mouthwashes on Candida albicans in patients with denture stomatitis. J Appl Oral Sci 18:291–296. https://doi.org/10.1590/S1678-77572010000300017

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pellon A, Sadeghi Nasab SD, Moyes DL (2020) New insights in Candida albicans innate immunity at the mucosa: toxins, epithelium, metabolism, and beyond. Front Cell Infect Microbiol 10:81–81. https://doi.org/10.3389/fcimb.2020.00081

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lee Y, Puumala E, Robbins N, Cowen LE (2020) Antifungal drug resistance: molecular mechanisms in Candida albicans and beyond. Chem Rev. https://doi.org/10.1021/acs.chemrev.0c00199

    Article  PubMed  PubMed Central  Google Scholar 

  13. Yadav AS, Kolluri G, Gopi M, Karthik K, Singh Y (2016) Exploring alternatives to antibiotics as health promoting agents in poultry-a review. J Exp Biol 4:3S-3S. https://doi.org/10.18006/2016.4(3S).368.383

    Article  Google Scholar 

  14. Doyle AA, Stephens JC (2019) A review of cinnamaldehyde and its derivatives as antibacterial agents. Fitoterapia 139:104405–104405. https://doi.org/10.1016/j.fitote.2019.104405

    Article  PubMed  Google Scholar 

  15. Mateen S, Rehman MT, Shahzad S, Naeem SS, Faizy AF, Khan AQ, Khan MS, Husain FM, Moin S (2019) Anti-oxidant and anti-inflammatory effects of cinnamaldehyde and eugenol on mononuclear cells of rheumatoid arthritis patients. Eur J Pharmacol 852:14–24. https://doi.org/10.1016/j.ejphar.2019.02.031

    Article  PubMed  Google Scholar 

  16. Daemi A, Lotfi M, Farahpour MR, Oryan A, Ghayour SJ, Sonboli A (2019) Topical application of Cinnamomum hydroethanolic extract improves wound healing by enhancing re-epithelialization and keratin biosynthesis in streptozotocin-induced diabetic mice. Pharm Biol 57:799–806. https://doi.org/10.1080/13880209.2019.1687525

    Article  PubMed  PubMed Central  Google Scholar 

  17. de Araújo MRC, Maciel PP, Castellano LRC, Bonan PRF, Alves DdN, de Medeiros ACD, de Castro RD (2021) Efficacy of essential oil of cinnamon for the treatment of oral candidiasis: a randomized trial. Spec Care Dentist. https://doi.org/10.1111/scd.12570

    Article  PubMed  PubMed Central  Google Scholar 

  18. da Nóbrega AD, Monteiro AFM, Andrade PN, Lazarini JG, Abílio GMF, Guerra FQS, Scotti MT, Scotti L, Rosalen PL, Castro RDd (2020) Docking prediction, antifungal activity, anti-biofilm effects on Candida spp., and toxicity against human cells of cinnamaldehyde. Molecules 25:5969–5969. https://doi.org/10.3390/molecules25245969

    Article  Google Scholar 

  19. Alves DdN, Martins RX, Ferreira EdS, Alves AF, Andrade JCd, Batista TM, Lazarini JG, Amorim LS, Rosalen PL, Farias DF, Castro RDd (2021) Toxicological parameters of a formulation containing cinnamaldehyde for use in treatment of oral fungal infections: an in vivo study. Biomed Res Int 2021:2305695. https://doi.org/10.1155/2021/2305695

    Article  PubMed  PubMed Central  Google Scholar 

  20. Friedman LM, Furberg CD, DeMets DL, Reboussin DM, Granger CB (2015) Fundamentals of clinical trials. Springer, London

    Book  Google Scholar 

  21. Gulati S, Desai J, Palackdharry SM, Morris JC, Zhu Z, Jandarov R, Riaz MK, Takiar V, Mierzwa M, Gutkind JS (2020) Phase 1 dose-finding study of metformin in combination with concurrent cisplatin and radiotherapy in patients with locally advanced head and neck squamous cell cancer. Cancer 126:354–362. https://doi.org/10.1002/cncr.32539

    Article  PubMed  Google Scholar 

  22. Nayar R and Wilbur DC (2018) Sistema Bethesda para Relato de Citologia Cervical: definições, critérios e notas explicativas. Book title. São Paulo: Livromed Paulista.

  23. Silva CS, Figueiredo S, de Oliveira PV, de Silva Saminez WF, Diniz RM, Rodrigues JFS, da Silva MSM, da Silva LCN, Grisotto MAG (2018) Óleo essencial da Canela (Cinamaldeído) e suas aplicações biológicas. Rev Investig Bioméd 9:192–197. https://doi.org/10.24863/rib.v9i2.143

    Article  Google Scholar 

  24. Zhang LW, Fu JY, Hua H, Yan ZM (2016) Efficacy and safety of miconazole for oral candidiasis: a systematic review and meta-analysis. Oral Dis 22:185–195. https://doi.org/10.1111/odi.12380

    Article  PubMed  Google Scholar 

  25. Isaac-Renton M, Li MK, Parsons LM (2015) Cinnamon spice and everything not nice: many features of intraoral allergy to cinnamic aldehyde. Dermatitis 26:116–121. https://doi.org/10.1097/DER.0000000000000112

    Article  PubMed  Google Scholar 

  26. Yanakiev S (2020) Effects of cinnamon (Cinnamomum spp.) in dentistry: a review. Molecules 25:4184–4184. https://doi.org/10.3390/molecules25184184

    Article  PubMed Central  Google Scholar 

  27. Hertel M, Schmidt-Westhausen AM, Strietzel F-P (2016) Local, systemic, demographic, and health-related factors influencing pathogenic yeast spectrum and antifungal drug administration frequency in oral candidiasis: a retrospective study. Clin Oral Investig 20:1477–1486. https://doi.org/10.1007/s00784-015-1631-0

    Article  PubMed  Google Scholar 

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Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoa de Nível Superior – Brasil (CAPES) – Finance Code: PROEX AUXPE—0521/2020.

Author information

Authors and Affiliations

  1. Department of Clinical and Social Dentistry, Graduate Program in Natural and Synthetic Bioactive Products (PgPNSB), Health Sciences Center, Federal University of Paraiba, João Pessoa, PB, Brazil

    Danielle da Nóbrega Alves

  2. Department of Clinical and Social Dentistry, Federal University of Paraiba, João Pessoa, Brazil

    Ana Karoline Vieira Melo & Maria Rejane Cruz de Araújo

  3. Department of Physiology and Pathology, Health Sciences Center, Federal University of Paraiba, João Pessoa, PB, Brazil

    Adriano Francisco Alves

  4. Health Sciences Center, Federal University of Paraiba, João Pessoa, PB, Brazil

    Rubens da Silva Araújo

  5. Department of Clinic and Social Dentistry, Health Sciences Center, Federal University of Paraiba, Campus I, João Pessoa, PB, 58051-970, Brazil

    Ricardo Dias de Castro

Authors
  1. Danielle da Nóbrega Alves
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  2. Ana Karoline Vieira Melo
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  3. Adriano Francisco Alves
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  4. Maria Rejane Cruz de Araújo
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  5. Rubens da Silva Araújo
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  6. Ricardo Dias de Castro
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Contributions

All authors contributed to the study conception and design. Material preparation and data collection and analysis were performed by Danielle da Nóbrega Alves, Ana Karoline Vieira Melo, Adriano Francisco Alves, Maria Rejane Cruz de Araújo, Rubens da Silva Araújo, and Ricardo Dias de Castro. The first draft of the manuscript was written by Danielle da Nóbrega Alves and all authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Ricardo Dias de Castro.

Ethics declarations

Ethics approval

All procedures followed the ethical standards of the Declaration of Helsinki, 1964. The study was submitted to the Research Ethics Committee (CEP) of the Health Sciences Center of the Federal University of Paraiba, being approved under opinion no. 3,892.294.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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da Nóbrega Alves, D., Melo, A.K.V., Alves, A.F. et al. Safety and tolerability of cinnamaldehyde in orabase for oral candidiasis treatment: phase I clinical trial. Clin Oral Invest 26, 4825–4833 (2022). https://doi.org/10.1007/s00784-022-04450-9

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  • DOI: https://doi.org/10.1007/s00784-022-04450-9

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