Sustained drug-delivery system: a promising therapy for denture stomatitis?

Dear Readers,

Denture-induced stomatitis is the most common type of oral candidosis and the most frequent mucosal alteration associated with complete or removable partial dentures in the elderly. Despite being an infection of multifactorial etiology, this condition has as main etiological factor the colonization of denture-bearing mucosa and acrylic bases by species of Candida spp., especially Candida albicans, found in 50 to 98% of all cases²⁵.

Different treatments are indicated for denture stomatitis, including topical antifungal and systemic therapy, care with oral hygiene, denture cleaning and disinfection procedures, replacement of old dentures, elimination of anatomic irregularities, re-establishment of atraumatic occlusion, removing the denture at night and nutritional restitution¹². Although systemic antifungal therapy is suggested for immunosuppressed patients, these drugs may present potential hepatotoxic and nephrotoxic effects and interaction with other drugs, thus increasing the adverse systemic effects⁶. Topical antifungal agents as nystatin and miconazole are largely used for the treatment of denture stomatitis¹²,¹⁵. These antifungal drugs are effective in relieving the clinical signs and symptoms of denture stomatitis associated with Candida spp.; however, they cannot reach a therapeutic antifungal concentration on the inner denture surfaces¹⁵. Consequently, re-infection of the treated oral mucosa may occur after conventional therapy with topical and systemic antifungal drugs. The high rates of clinical relapse and recurrence in up to two weeks post-treatment make the treatment of denture stomatitis challenging¹⁵,¹⁸.

Factors other than inability to maintain therapeutic concentrations of antifungal drugs on the surface of dentures are associated with failure of conventional antifungal therapy including the following: 1) reduction of antifungal action by salivary flow and swallowing, and tongue movements; 2) lack of patient compliance to antifungal therapy due to costs required for the medications, unpleasant taste of topical agents, continuous utilization of dentures and strict drug regimen; 3) persistent contact between injured mucosa and contaminated internal denture surfaces, which favors re-infection of the mucosa and causes trauma to supporting tissues, extending the clinical course of the pathology²⁰,²¹.

An effective treatment of denture stomatitis requires a therapy based on the sustained release of antifungal drugs that may reach adequate therapeutic concentration to significantly reduce the Candida from both the supporting tissues and infected denture surfaces. In this context, incorporation of antifungal/antimicrobial agents into denture base materials to be progressively released to the oral cavity has been suggested to prevent biofilm accumulation, inhibit C. albicans colonization, and contribute to the treatment of denture stomatitis⁵,²⁰,²¹. This protocol requires only the use of dentures by patients, thus reducing the need for patient compliance to antifungal drug regimens²¹. Furthermore, the incorporation of drugs into denture liners breaks the contact between the denture biofilm and infected tissues, thus avoiding a cycle of re-infection via prostheses¹⁴. In this regard, the use soft lining materials is highly recommended as it results in the recovery of injured tissues and patient comfort¹⁴. However, soft lining materials, mainly short-term ones as tissue conditioners and temporary resilient liners are easily degradable and susceptible to microbial colonization¹⁷. Therefore, the modification of these temporary materials by antimicrobial agents also has the advantage of increasing their clinical longevity. As life cycle of short-term soft liners is approximately 14 days, the treatment period of denture-induced stomatitis using these materials modified by drugs is similar to the period required when conventional topical antifungal agents are used²⁰,²¹. As a result, denture stomatitis can be treated before replacing temporary soft liners with long-term liners or fabricating new dentures, in a relatively short period.

Although incorporation of antifungal/antimicrobial agents at commercially available concentrations to polymeric/plastic materials can effectively inhibit the growth of C. albicans²⁰,²¹, it may affect their morphological structure²⁴ and properties such as tensile strength¹,²², water absorption⁷, modulus of elasticity and weight¹, hardness¹,²⁰,²³, roughness²³, and peel bond strength to denture base resin². In an order to provide lower concentrations of drugs to these materials without severely compromising their properties, Bueno, et al.⁵ determined minimum inhibitory concentrations (MICs) of C. albicans biofilm for antifungal/antimicrobial agents added to a temporary resilient liner and a tissue conditioner. The five drugs (nystatin, miconazole, ketoconazole, itraconazole, and chlorhexidine diacetate) incorporated at MICs into both soft materials were effective in inhibiting the growth of C. albicans for up to 14 days.

Considering the promising results of Bueno, et al.⁵, some studies were performed to evaluate the effects of drug addition at MICs on important properties of these materials. With the exception of itraconazole, the MICs of drugs incorporated into temporary soft lining materials resulted in minimal changes in their peel bond strength to a denture base resin within 14 days¹⁹. After 14 days, the MICs of nystatin and ketoconazole in both materials and chlorhexidine in temporary resilient liner did not significantly influence their water sorption¹⁰. The solubility of both resilient materials was not modified by nystatin at MIC within 14 days¹⁰. Also, in this issue, Lima, et al.¹¹ observed that the addition of drugs at MICs resulted in no harmful effects for the porosity of both soft lining materials in different periods of water immersion, except for chlorhexidine and nystatin in the tissue conditioner and chlorhexidine in the temporary resilient liner at 14 days. Despite these favorable outcomes, before the incorporation of drugs at MICs may be indicated as an alternative therapy for denture stomatitis, it is necessary to evaluate the biocompatibility of this protocol with the oral tissues. During their life cycle, polymeric/plastic materials release soluble substances in the oral environment, which may be potentially toxic, such as methyl methacrylate and dibutyl phthalate. When released in saliva, these components may even act at sites distant from the area contacting the material⁹,¹⁶. These possible cytotoxic effects have been assessed in vitro by using mouse fibroblast culture⁹,¹⁶, which is clinically restricted, since the effects of tests performed directly on cells are more marked than the oral conditions in vivo. In addition, the limited literature available on the in vivo biocompatibility of denture base liners with oral tissues in animal models showed an increased thickness of the stratum corneum layer for rats receiving acrylic intraoral device relined with non-modified temporary resilient material³,⁴. Nevertheless, there is lack of information on the biocompatibility of drug-modified denture liners with oral tissues in animal models.

From the in vitro studies evaluated, it is possible to conclude that the modification of temporary resilient materials by antifungal/antimicrobial agents, especially in lower concentrations, may represent a viable protocol for in vivo treatment of denture stomatitis during a period similar to the conventional therapy with topical antifungals (14 days). However, it is important to emphasize that when in the mouth, denture resilient liners may be subjected to additional thermal stress, pH range, and occlusal load, which could lead to other pattern of properties of these products. This might explain the evidence that the magnitude and speed of all changes in material properties after immersion in distilled water (as done in all in vitro studies on the properties of modified soft liners) are different from those observed in clinical condition¹³. Nevertheless, no evidence was found to confirm how each of these factors affect the evaluated properties. Moreover, the loss of leachable components is faster when the soft liner is in the mouth due to the oral environment, food, and cleaning methods adopted by the patient¹³.

Considering the aspects described previously, before clinical indication of this protocol for denture stomatitis treatment, future in vitro studies are necessary to evaluate other relevant properties of modified soft liners such as daily drug release and drug pattern of incorporation. Furthermore, the findings of animal model studies on temporary resilient liners should not be considered enough for clinical indication of a material or treatment, since important factors as removal and hygiene of the appliances and deformation due to occlusal load in normal feeding conditions were not analyzed. Thus, after observations of in vitro studies on other properties of modified materials as well in vivo studies on animal models testing this protocol, clinical trials in humans are necessary to allow the safe indication of drug incorporation in temporary resilient liners as optimal antifungal delivery for denture stomatitis treatment.

REFERENCES

• ¹
  - Addy M, Handley R. The effects of the incorporation of chlorhexidine acetate on some physical properties of polymerized and plasticized acrylics. J Oral Rehabil 1981;8:155-163.
• ²
  - Alcântara CS, de Macedo AF, Gurgel BC, Jorge JH, Neppelenbroek KH, Urban VM. Peel bond strength of resilient liner modified by the addition of antimicrobial agents to denture base acrylic resin. J Appl Oral Sci. 2012;20:607-12.
• ³
  - Bail M, Meister LM, Campagnoli EB, Jorge JH, Ban Mde C, Sanchez-Ayala A, et al. Histopathological changes by the use of soft reline materials: a rat model study. PLoS One. 2014;9:e100293.
• ⁴
  - Barclay SC, MacDonald DG, Watson IB. The effect of chairside relining materials on rat palatal mucosa. J Dent. 1997;25:251-55.
• ⁵
  - Bueno MG, Urban VM, Barberio GS, da Silva WJ, Porto VC, Pinto L, et al. Effect of antimicrobial agents incorporated into resilient denture relines on the Candida albicans biofilm. Oral Dis. 2015;21:57-65.
• ⁶
  - Choi YH, Lee U, Lee BK, Lee MG. Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2. Br J Pharmacol. 2010;16:815-29.
• ⁷
  - Douglas WH, Clarke DA. Physical and mechanical properties of nystatin-containing denture liners. J Prosthet Dent 1975;34:428-434.
• ⁸
  - Graham BS, Jones DW, Sutow EJ. Clinical implications of resilient denture lining material research. Part II: Gelation and flow properties of tissue conditioners. J Prosthet Dent. 1991;65:413-8.
• ⁹
  - Lefebvre CA, Wataha JC, Cibirka RM, Schuster GS, Parr GR. Effects of triclosan on the cytotoxicity and fungal growth on a soft denture liner. J Prosthet Dent. 2001;85:352-6.
• ¹⁰
  - Lima JF, Maciel JG, Arrais CA, Porto VC, Urban VM, Neppelenbroek KH. Effect of incorporating antifungals on the water sorption and solubility of interim resilient liners for denture base relining. J Prosthet Dent. 2016;115:611-6.
• ¹¹
  - Lima JF, Maciel JG, Hotta J, Vizoto ACP, Honorio HM, Urban VM, Neppelenbroek KH. Porosity of temporary denture soft liners containing antifungal agents. J Appl Oral Sci. 2016;24:
• ¹²
  - Lombardi T, Budtz-Jorgensen E. Treatment of denture-induced stomatitis: a review. Eur J Prosthodont Restor Dent 1993;2:17-22.
• ¹³
  - Mante FK, Mante MO, Petropolous VC. In vitro changes in hardness of sealed resilient lining materials on immersion in various fluids. J Prosthodont. 2008;17:384-91.
• ¹⁴
  - Marin Zuluaga DJ, Gomez Velandia OC, Rueda Clauijo DM. Denture-related stomatitis managed with tissue conditioner and hard autopolymerising reline material. Gerodontology. 2011;28:258-63.
• ¹⁵
  - Neppelenbroek KH, Pavarina AC, Palomari Spolidorio DM, Sgavioli Massucato EM, Spolidorio LC, Vergani CE. Effectiveness of microwave disinfection of complete dentures on the treatment of Candida-related denture stomatitis. J Oral Rehabil. 2008;35:836-46.
• ¹⁶
  - Ozdemir KG, Yilmaz H, Yilmaz S. In vitro evaluation of cytotoxicity of soft lining materials on L929 cells by MTT assay. J Biomed Mater Res B Appl Biomater. 2009;90:82-6.
• ¹⁷
  - Pisani MX, da Silva CH, Paranhos HF, Souza RF, Macedo AP. Evaluation of experimental cleanser solution of Ricinus communis: effect on soft denture liner properties. Gerodontology. 2012;29:e179-85.
• ¹⁸
  - Ramage G, Tomsett K, Wickes BL, Lopez-Ribot JL, Redding SW. Denture stomatitis: a role for Candida biofilms. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98:53-59.
• ¹⁹
  - Sánchez-Aliaga A, Pellissari CV, Arrais CA, Michél MD, Neppelenbroek KH, Urban VM. Peel bond strength of soft lining materials with antifungal to a denture base acrylic resin. Dent Mater J. 2016;35:194-203
• ²⁰
  - Schneid TR. An in vitro analysis of a sustained release system for the treatment of denture stomatitis. Spec Care Dentist. 1992;12:245-50.
• ²¹
  - Truhlar MR, Shay K, Sohnle P. Use of a new assay technique for quantification of antifungal activity of nystatin incorporated in denture liners. J Prosthet Dent. 1994;71:517-24.
• ²²
  - Urban VM, de Souza RF, Arrais CA, Borsato KT, Vaz LG. Effect of the association of nystatin with a tissue conditioner on its ultimate tensile strength. J Prosthodont. 2006;15:295-9.
• ²³
  - Urban VM, Lima TF, Bueno MG, Giannini M, Arioli Filho JN, de Almeida AL, et al. Effect of the addition of antimicrobial agents on Shore A hardness and roughness of soft lining materials. J Prosthodont. 2015;24:207-14.
• ²⁴
  - Urban VM, Seo RS, Giannini M, Arrais CA. Superficial distribution and identification of antifungal/antimicrobial agents on a modified tissue conditioner by SEM-EDS microanalysis: a preliminary study. J Prosthodont. 2009;18:603-10.
• ²⁵
  - Zomorodian K, Haghighi NN, Rajaee N, Pakshir K, Tarazooie B, Vojdani M, Sedaghat F, Vosoghi M. Assessment of Candida species colonization and denture-related stomatitis in complete denture wearers. Med Mycol 2011;49:208-11.

Publication Dates

• Publication in this collection
  Sep-Oct 2016