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Phytomedicines for Candida-associated denture stomatitis
Fitoterapia 81 (2010) 323–328
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Fitoterapia j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / f i t o t e
Review
Phytomedicines for Candida-associated denture stomatitis Ana Regina Casaroto, Vanessa Soares Lara ⁎ Department of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
a r t i c l e
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a b s t r a c t
Article history: Received 30 July 2009 Accepted in revised form 1 December 2009 Available online 16 December 2009
Phytomedicines are becoming more popular all over the world. Denture stomatitis (DS) presents as an inflammatory reaction in denture-bearing patients, under maxillary prosthesis with Candida albicans being the principal etiological agent. Many different methods of treatment for DS have been observed. The effects of the main medicinal plants claimed to be useful as antifungal agents in the treatment of DS are reviewed. Herbal remedies that have shown potential promise are mentioned, although much research is still required. © 2009 Elsevier B.V. All rights reserved.
Keywords: Candida albicans Denture stomatitis Phytomedicines Propolis
Contents 1. 2.
Introduction . . . . . . . . Medicinal plants . . . . . . 2.1. Propolis . . . . . . 2.2. Punica granatum . . 2.3. Streblus asper . . . . 2.4. Azadirachta indica . . 2.5. Vitis vinifera . . . . 2.6. Melaleuca alternifolia 3. Conclusion . . . . . . . . References . . . . . . . . . . .
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1. Introduction Denture stomatitis (DS) is an inflammatory reaction of the palatal and alveolar mucosa underlying removable dental prostheses [1]. This stomatitis is more commonly seen in the
⁎ Corresponding author. Bauru Dental School, University of São Paulo, Department of Stomatology (Oral Pathology), Rua Octávio Pinheiro Brisola, 9-75, Vila Universitária, 17012-901 Bauru, SP, Brazil. Tel.: + 55 14 3235 8251; fax: + 55 14 3223 4679. E-mail addresses: [email protected] (A.R. Casaroto), [email protected] (V.S. Lara). 0367-326X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.fitote.2009.12.003
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maxillary mucosa than in the mandibular mucosa [2]. The prevalence of this inflammatory reaction has been shown to vary from 15% to 65% [2], and in complete denture wearers in Brazil, from 19.5% to 50.6% [3,4]. This disease has a multifactorial etiology, and poor hygiene and continuous denture wearing have been the most frequent causes associated with it. The latter two factors facilitate denture plaque formation, in which the fungi Candida albicans can be regularly isolated, suggesting a pathogenic association between bacteria and fungi [5]. Furthermore, numerous yeasts are commonly found on the palatal surface of the denture, which supports the theory that the maxillary denture acts as a
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reservoir enabling Candida to re-infect the mucosal surface continually [6]. Different methods of treatment for DS have been suggested. Treatment regimens include relining with tissue conditioners [7], chemical substances such as chlorhexidine and sodium hypochlorite [8], efficient denture hygiene and the removal of dentures at night [9]. Association of these procedures with topical application of antifungal agents on the affected areas and on dentures is relevant as well [2,10]. The most common drugs used are imidazole compounds (miconazole) [11], polyenic derivatives (nystatin), and amphotericin B [12]. However, toxicity and resistance to these antifungal drugs are problems to which variable results have been observed and the recurrence rate is high. Natural products have proved to be an alternative to synthetic chemical substances and the interest in medicinal plants as a source of antimicrobial agents has grown dramatically. A wide variety of plant extracts have been reported to have antifungal activity against C. albicans [6,9,13–16]. In addition, these medicinal plants may play a very important role in the treatment of DS. This article reviews medicinal plants with antifungal property against C. albicans that may be suggested as promising alternative for treatment of DS. 2. Medicinal plants 2.1. Propolis Propolis is a resinous substance derived from tree exudates mixed with floral sap, bee salivary secretions, wax, and pollen. It is used by bees for thermal insulation, sealing, and protecting the hive against microorganisms [17]. Its complex chemical composition is dependent on the plant source and local flora [18,19]. The compounds comprising propolis include volatile oils (5–10%), waxes (30–40%), resins, balsams, and pollen grains, which are rich sources of essential elements such as magnesium, nickel, calcium, iron, and zinc. Polyphenols have been identified as the main organic constituents of propolis, mainly represented by flavonoids and accompanied by phenolic acids, esters, phenolic aldehydes, and ketones [20]. Although propolis samples of different origins have different compositions, they have similar antimicrobial effects [21] because this effect is of prime importance to the survival of the hive. Propolis has remarkable antibacterial
[22,23], antifungal [23], anti-inflammatory [23,24], antioxidant [25,26], and immunomodulatory properties [20]. Dental studies have evaluated the biological activity of propolis, mainly with respect to the healing process [27,28], inhibition of dental plaque formation and prevention of dental caries [29,30], and as an intracanal medication in endodontic treatment [23]. Phenolic compounds, such as flavonoids, are the main components responsible for the functional properties of propolis [19,21]. However, the decrease in the content of phenolic compounds is not accompanied by a decrease in activity [21]. Obviously, there are other compounds that contribute to the biological activity in this case. Furthermore, propolis extraction methods may influence its activity, since different solvents solubilize and extract different compounds [18,20]. The most common extracts used in biological assays are ethanol, in different concentrations, methanol and water [18]. The seasonal variations in propolis composition are not significant and bees do not change its chemical composition in a specific geographic region because they visit essentially the same vegetal sources [18]. Many authors have studied the antifungal activity of propolis against C. albicans (Table 1) [13,17,21,31,32] and the ethanol extract has shown one of the best activities [13,20,31]. Furthermore, although flavonoid compounds have been considered responsible for the inhibitory effect on yeast, this effect could also be due to a different class of compounds [13]. The antimicrobial activity of propolis may occur through direct action against microorganisms and indirectly as well via stimulation of the immune system and further microorganism killing. The ultrastructural findings seen in scanning electron micrography suggested that the antifungal activity of propolis is due to changes in the cell wall leading to an increase in volume and cell membrane rupture [33]. Sforcin [18] states that propolis may activate macrophages, increasing their microbicidal activity. Among several biological activities described for propolis, antifungal and anti-inflammatory activities suggest its possible use in the local treatment of DS (Table 1) [9,34]. Despite the increasing use of propolis worldwide, only a few studies have been conducted to determine the therapeutic effect of propolis against this oral condition. Santos et al. [34] studied the topical therapeutic effect of ethanol extract of propolis on oral candidiasis associated with stomatitis caused by wearing dentures, and observed regression of lesions in all patients treated. Moreover, in another research, the authors evaluated
Table 1 Biological activity of propolis samples against Candida albicans. Authors
Propolis samples
Extract
Antifungal activity
Kujumgiev et al. [21]
Prudentopolis, Parana State, Brazil Pacajus, Ceara State, Brazil Limera, São Paulo State, Brazil Ribeirão Preto, São Paulo State, Brazil
Ethanolic extract 70%
In vitro
Ethanolic Ethanolic Ethanolic Ethanolic
In vitro
Sawaya et al. [13]
Silici et al. [31]
Santos et al. [34] Santos et al. [9]
Adana, South Anatolia, Turkey Kayseri, Central Anatolia, Turkey Artvin, North Anatolia, Turkey Minas Gerais State, Brazil Minas Gerais State, Brazil
extract extract extract extract
70% 50% 30% 80%
In vitro
Ethanolic extract 80% Ethanolic extract 90%
In vivo In vivo
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the clinical efficacy of an ethanol-free propolis gel formulation in patients diagnosed with DS. This propolis gel presented mucoadhesive properties and all patients showed complete remission of palatal edema and erythema after one week of treatment [9]. The results of the study of Ceschel et al. [27], who investigated a topical mucoadhesive gel containing propolis, showed that propolis is soluble in hydroxylic solvents such ethanol and propylene glycol. Ethanol has a very low viscosity and rapidly solubilizes propolis, but this solvent causes mucosal irritations and for this reason its use in formulations has been avoided. Propolis is relatively soluble in propylene glycol but with very low dissolution kinetics, perhaps due to the high viscosity of this solvent. Surfactants, such as polysorbate, significantly improve propolis solubility. For this reason, a polysorbate solution in propylene glycol has been chosen as a gel solvent. In order to obtain a mucoadhesive gel formulation, the polymer hydroxypropyl cellulose has been chosen because it shows the best gelling and mucoadhesive properties. Finally, the resultant product is obtained by dropping water to a minimum to formulate a sticky solution. This propolis gel formulation has been show to be an alternative topical choice for the treatment of DS [9]. Biological activities of others plants against C. albicans are summarized in Table 2. 2.2. Punica granatum Pomegranate (P. granatum) is a rich source of anthocyanins and other phenolic compounds that have strong antioxidant activity. The edible parts of pomegranate fruit (about 80% of total fruit weight) comprise 80% juice and 20% seed. Pomegranate fruit extract is a rich source of 2 types of polyphenolic compounds: anthocyanins, which give red color to the fruit and juice, and hydrolysable tannins, which account for 92% of the anti-oxidant activity of the whole fruit [35]. Pomegranate juice has many biological effects, some of which may have important clinical implications. Anti-atherogenic [36], anti-oxidant, anti-tumor [37] and virucidal [38] effects have been reported for P. granatum. In addition, the antimicrobial activity of this fruit has been widely investigated. The findings of several studies, including some relating to inhibition of adherence, suggest that oral bacteria and C. albicans are sensitive to the extract of P. granatum [39–41]. The action of tannins against yeasts can be established by a relationship between their molecular structure and
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their toxicity, astringent properties or other mechanisms still not well clarified. The effect of tannins on microbial metabolism can be measured by their action on membranes. They can cross the cell wall, composed of several polysaccharides and proteins, and bind to its surface [41]. In general, polyphenols certainly interfere in salivary proteins and some oral bacterial enzymes. They may affect microorganism membranes and disturb microorganism coaggregation [10]. Although P. granatum do not exhibit well established fungicidal or fungistatic activity, this therapeutic agent may inhibit yeast adherence by other mechanisms and can represent a new perspective in the combat and control of DS. Up to now, the P. granatum gel used in investigations against candidosis was prepared with the bark of fresh fruits. The basic gel consists of carbopol, water, triethanolamine and 0.5 ml of the raw extract, equivalent to 540 mg of the plant powder [10,41]. In the first clinical trial, patients with DS applied the gel on the lesions, and negativity of yeasts was observed in most subjects. Therefore, this P. granatum extract gel against candidosis-associated DS may be used as a topical antifungal agent for the treatment this disease [10]. In another study, the authors evaluated the antimicrobial effect of this phytotherapic gel on the adherence of C. albicans to glass. Adherence to glass observed in this study was similar to that occurring on prosthetic surfaces and this phytotherapeutic agent might be used to control the adherence of different microorganisms in the oral cavity [41]. 2.3. Streblus asper Streblus asper Lour (Moraceae) is a small tree, indigenous to tropical countries such as India, Sri Lanka, Malaysia, the Philippines and Thailand. It is also known as the tooth brush tree [42]. The compounds comprising S. asper include volatile oils. This ethnomedicinal plant is a rich source of cardiac glycosides, and asperoside, strebloside and mansoni are the few active compounds that have been isolated from this plant [43]. This medicinal plant is used for several pharmaceutical purposes. Different parts of S. asper have been found to exhibit cardiotonic, antifilarial, anticancer, antimicrobial, anti-allergic and antimalarial activities [43]. Among several others biological activities, its extract has been used for relief of fever, dysentery, toothache and gingivitis [44]. In addition, bactericidal activity was found in the 50% ethanol extract of its leaves [42]. In spite of its many beneficial
Table 2 Biological activity of plants against Candida albicans. Authors
Scientific name
Vasconcelos et al. [41]
Punica granatum Linn –
Taweechaisupapong et al. [6] Streblus asper Polaquini et al. [15] Han [16] Catalán et al. [2] (–) not informed.
Azadirachta indica Vitis vinifera Melaleuca alternifolia
Extract
Mechanisms of action
Astringent properties Cross the cell wall Disturb microorganism co-aggregation Ethanolic extract Reduce the ability to induce germ tube formation Changes in cell surface hydrophobicity Aqueous extract Changes in cell surface hydrophobicity Ethanolic extract Inhibition of fungal growth The Australian Tea Tree Oil Research Institute Ltd., Inhibitory to yeast growth Australia
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properties, 50% S. asper leaf ethanolic extract (SAE) [42] or at concentration ≤ 250 mg/ml [44] was shown to have no fungicidal activity against C. albicans. However, these sublethal concentrations of extract can block the adherence of Candida to human oral epithelial cells in vitro [44]. In another research, Taweechaisupapong et al. [6] observed that the exposure of C. albicans to sublethal concentrations of SAE resulted in a reduction in the ability of the yeasts to adhere to denture acrylic resin. Therefore, although S. asper does not have fungicidal property against C. albicans, it may possibly be a preventative for DS. Studies up to now have presented results related to the extracts only. Further studies are required to clarify the use of possible formulations incorporated into SAE. On the basis mechanisms of action, SAE reduced the ability to induce germ tube formation, inhibited Candida germination and reduced attachment to human epithelial cells [44]. Thus, the inhibition of germ tube formation by the SAE is important, since it is well known that germ tube and mycelial forms of C. albicans adhere more efficiently to host cells than do yeast form cells [45]. It is likely that the extract affect the Candida cell wall. Moreover, since cell surface hydrophobicity (CSH) is the major factor for Candida adherence to inert polymer [46], it is possible that SAE interferes with any changes in CSH, which would result in a shift in the free energy of interaction of the cell with the target surface, thereby reducing candidal adhesion [6]. 2.4. Azadirachta indica Azadirachta indica, commonly known as neem, is a tree native to the Indian subcontinent and Southeast Asia. The compounds isolated from this tree may be divided into two major classes: isoprenoids (diterpenoids and triterpenoids) and non-isoprenoids, which include proteins, amino acids, carbohydrates, sulfur compounds, polyphenolics such as flavonoids and others [47]. Neem has attracted worldwide attention in recent years, owing to its wide range of medicinal properties. Its constituents have been shown to have immunomodulatory, anti-inflammatory, antifungal, antibacterial, antiviral and anti-oxidant properties as their main biological activities [48]. In addition, the extract from A. indica is a powerful inhibiting agent against microorganisms that cause infectious diseases in the oral cavity, such as C. albicans. However, Neem aqueous extract does not seem to have a fungicidal effect against this fungus due to the low concentrations of the bioactive compounds, which may be increased when alcoholic extracts are involved [15]. Polaquini et al. [15] observed that C. albicans showed visible aggregation when incubated with Neem extract. The self-aggregation of yeast observed after the addition of the extract may be explained by the pronounced increase in hydrophobicity. Nevertheless, a decrease in adhesion capacity of cells to composite resin was also recorded. Thus, the study reinforces the possible anti-adhesive nature of the plant extract effect on the prevention of diseases of the oral cavity, although further clinical studies are needed before it is used. Moreover, the possibility of incorporating the extract into formulations for the treatment of candida-associated DS should also be studied.
2.5. Vitis vinifera Vitis vinifera (Common Grape Vine) is a species of Vitis bearing the fruit known as a grape and cultivated on every continent. Grape seeds are waste products of the winery and grape juice industry. These seeds contain lipids, proteins, carbohydrates, and 5–8% polyphenols, depending on the variety [49]. Polyphenols in grape seeds are mainly monomeric, oligomeric flavanols [50] and proanthocyanidins [51]. Grape seed extract (GSE) has been reported to exert protective effects against various forms of disease. GSE have demonstrated excellent free-radical scavenging [52]. In most cases, GSE activities are related to its anti-oxidant properties, mainly attributed to the phenolic compounds such as catechin and low-molecular proanthocyanidin [49]. Monomeric flavonols are directly implicated in the suppression of degenerative diseases such as cancer and atherosclerosis [50]. Furthermore, monomeric, phenolic and proanthocyanidin compounds act as antimutagenic and antiviral agents [51]. Nair et al. [53] believe that the immunomodulatory activities mediated by GSE may be due its product in which oligomers predominate. Several studies also have mentioned the antifungal activity of GSE against C. albicans [16,53–55]. Han [16] has shown that GSE enhances the resistance of mice against the disseminated candidiasis due to C. albicans. Moreover, the authors have observed that the polyphenolic compound epigallocatechin gallate (EGCG) present in GSE causes inhibition of C. albicans yeast cell growth. EGCG may function as anti-oxidants and cause oxidative-stress-related responses in yeast cells by the reactive oxygen species H2O2 [54]. Indeed, the grape seed contains many types of polyphenols, ranging from monomers to oligomers, which may induce differential effects on IFN-γ production and thus GSE selectively induces the production of Th1-derived cytokine IFN-γ [53]. In addition, IFN-γ enhances the NADPH oxidase activity involved in dendritic cell stimulation and increases the candida-killing activity in these cells [55]. Thus, these evidences suggest that GSE can be applied as a phytomedicine for the treatment of candidal infection. The grape seed has been studied only as an extract. The powdered seed material has been used to obtain 70% ethanol extracts, and the filtrate condensed and prepared in Dulbecco's Phosphate Buffered Saline (DPBS) solution [16]. Further studies with regard to formulations incorporated into GSE should be developed so that its use may be indicated as a topical antifungal agent against candidosis-associated DS. 2.6. Melaleuca alternifolia Tea tree oil (TTO) is the essential oil steam-distilled from the Australian native plant M. alternifolia. It is a complex mixture composed of approximately 100 monoterpene and sesquiterpene hydrocarbons and alcohols [56]. The oil is reported to have a range of medicinal properties, including antimicrobial, anti-inflammatory and analgesic effects [57,58]. TTO has been used as a natural topical antifungical agent due to its lipophylic nature, which facilitates skin penetration [2]. In this context, it has been clinically evaluated for the treatment of several superficial fungal infections, including onychomycosis [59], tinea [60] and refractory oral candidiasis [61].
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Hammer et al. [58] observed in vitro that the TTO reversibly inhibits the germ tube formation by C. albicans in the presence of, or pre-exposure to sub-inhibitory concentrations (0.25%) of TTO. These findings may be due to the effects of essential oils on cellular membrane properties and membrane-associated functions [62], including the inhibition of respiration [58]. Moreover, inhibition of respiration in yeast cells has been demonstrated by terpenic oil components [63], and consequent inhibition of germ tube formation by C. albicans by terpenes eugenol and vanillin [64]. Given the putative increased virulence of hyphae in comparison with blastoconidia, the inhibition of hyphal development is an advantageous characteristic for a therapeutic agent. TTO affects the ability of blastoconidia to germinate [58] and this may have therapeutic implication in the treatment of DS. This is consistent with Catalán et al. [2] who reported that in vitro 20% (vol/vol) of TTO mixed with either Coe-comfort or Fitt tissue conditioners has both inhibitory and fungicidal activity against C. albicans. In addition, the authors observed that patients treated with TTO mixed with Coe-Comfort showed decrease in palatal inflammation. These finding reinforce the idea that TTO could be used as an alternative therapy for DS resistant to traditional therapies. However, future research should still be performed to determine possible formulation issues related to the use of essential oil of M. alternifolia for the treatment of DS. 3. Conclusion Against this background, some phytomedicines can be suggested for the treatment of the candidal infection and consequently for DS. Nevertheless, further research is needed in order to clarify the antifungal mechanism of these extracts under different conditions. In addition, further clinical studies are required before they are used. Current opinion is that for their safe use, it is important to have standardized preparations of medicinal plant medications, which may be less toxic than many synthetic medicines. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.fitote.2009.12. 0036. References [1] Darwazeh AM, Al-Refai S, Al-Mojaiwel S. J Prosthet Dent 2001;86: 420–3. [2] Catalán A, Pacheco JG, Martínez A, Mondaca MA. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:327–32. [3] Pires FR, Santos EB, Bonan PR, De Almeida OP, Lopes MA. J Oral Rehabil 2002;29:1115–9. [4] Marchini L, Vieira PC, Bossan TP, Montenegro FL, Cunha VP. Gerodontology 2006;23:33–7. [5] Espinoza I, Rojas R, Aranda W, Gamonal J. J Oral Pathol Med 2003;32: 571–5. [6] Taweechaisupapong S, Klanrit P, Singhara S, Pitiphat W, Wongkham S. J Ethnopharmacol 2006;106:414–7. [7] Kulak Y, Kazazoglu E. J Oral Rehabil 1998;25:135–8. [8] Barnabé W, De Mendonça Neto T, Pimenta FC, Pegoraro LF, Scolaro LM. J Oral Rehabil 2004;31:453–9. [9] Santos VR, Gomes RT, Mesquita RA, Moura MDG, França EC, Aguiar EG, Naves MD, Abreu JAS, Abreu SRL. Phytother Res 2008;22:1544–7.
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Fitoterapia j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / f i t o t e
Review
Phytomedicines for Candida-associated denture stomatitis Ana Regina Casaroto, Vanessa Soares Lara ⁎ Department of Oral Pathology, Bauru School of Dentistry, University of São Paulo, Bauru, SP, Brazil
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 30 July 2009 Accepted in revised form 1 December 2009 Available online 16 December 2009
Phytomedicines are becoming more popular all over the world. Denture stomatitis (DS) presents as an inflammatory reaction in denture-bearing patients, under maxillary prosthesis with Candida albicans being the principal etiological agent. Many different methods of treatment for DS have been observed. The effects of the main medicinal plants claimed to be useful as antifungal agents in the treatment of DS are reviewed. Herbal remedies that have shown potential promise are mentioned, although much research is still required. © 2009 Elsevier B.V. All rights reserved.
Keywords: Candida albicans Denture stomatitis Phytomedicines Propolis
Contents 1. 2.
Introduction . . . . . . . . Medicinal plants . . . . . . 2.1. Propolis . . . . . . 2.2. Punica granatum . . 2.3. Streblus asper . . . . 2.4. Azadirachta indica . . 2.5. Vitis vinifera . . . . 2.6. Melaleuca alternifolia 3. Conclusion . . . . . . . . References . . . . . . . . . . .
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1. Introduction Denture stomatitis (DS) is an inflammatory reaction of the palatal and alveolar mucosa underlying removable dental prostheses [1]. This stomatitis is more commonly seen in the
⁎ Corresponding author. Bauru Dental School, University of São Paulo, Department of Stomatology (Oral Pathology), Rua Octávio Pinheiro Brisola, 9-75, Vila Universitária, 17012-901 Bauru, SP, Brazil. Tel.: + 55 14 3235 8251; fax: + 55 14 3223 4679. E-mail addresses: [email protected] (A.R. Casaroto), [email protected] (V.S. Lara). 0367-326X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.fitote.2009.12.003
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maxillary mucosa than in the mandibular mucosa [2]. The prevalence of this inflammatory reaction has been shown to vary from 15% to 65% [2], and in complete denture wearers in Brazil, from 19.5% to 50.6% [3,4]. This disease has a multifactorial etiology, and poor hygiene and continuous denture wearing have been the most frequent causes associated with it. The latter two factors facilitate denture plaque formation, in which the fungi Candida albicans can be regularly isolated, suggesting a pathogenic association between bacteria and fungi [5]. Furthermore, numerous yeasts are commonly found on the palatal surface of the denture, which supports the theory that the maxillary denture acts as a
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reservoir enabling Candida to re-infect the mucosal surface continually [6]. Different methods of treatment for DS have been suggested. Treatment regimens include relining with tissue conditioners [7], chemical substances such as chlorhexidine and sodium hypochlorite [8], efficient denture hygiene and the removal of dentures at night [9]. Association of these procedures with topical application of antifungal agents on the affected areas and on dentures is relevant as well [2,10]. The most common drugs used are imidazole compounds (miconazole) [11], polyenic derivatives (nystatin), and amphotericin B [12]. However, toxicity and resistance to these antifungal drugs are problems to which variable results have been observed and the recurrence rate is high. Natural products have proved to be an alternative to synthetic chemical substances and the interest in medicinal plants as a source of antimicrobial agents has grown dramatically. A wide variety of plant extracts have been reported to have antifungal activity against C. albicans [6,9,13–16]. In addition, these medicinal plants may play a very important role in the treatment of DS. This article reviews medicinal plants with antifungal property against C. albicans that may be suggested as promising alternative for treatment of DS. 2. Medicinal plants 2.1. Propolis Propolis is a resinous substance derived from tree exudates mixed with floral sap, bee salivary secretions, wax, and pollen. It is used by bees for thermal insulation, sealing, and protecting the hive against microorganisms [17]. Its complex chemical composition is dependent on the plant source and local flora [18,19]. The compounds comprising propolis include volatile oils (5–10%), waxes (30–40%), resins, balsams, and pollen grains, which are rich sources of essential elements such as magnesium, nickel, calcium, iron, and zinc. Polyphenols have been identified as the main organic constituents of propolis, mainly represented by flavonoids and accompanied by phenolic acids, esters, phenolic aldehydes, and ketones [20]. Although propolis samples of different origins have different compositions, they have similar antimicrobial effects [21] because this effect is of prime importance to the survival of the hive. Propolis has remarkable antibacterial
[22,23], antifungal [23], anti-inflammatory [23,24], antioxidant [25,26], and immunomodulatory properties [20]. Dental studies have evaluated the biological activity of propolis, mainly with respect to the healing process [27,28], inhibition of dental plaque formation and prevention of dental caries [29,30], and as an intracanal medication in endodontic treatment [23]. Phenolic compounds, such as flavonoids, are the main components responsible for the functional properties of propolis [19,21]. However, the decrease in the content of phenolic compounds is not accompanied by a decrease in activity [21]. Obviously, there are other compounds that contribute to the biological activity in this case. Furthermore, propolis extraction methods may influence its activity, since different solvents solubilize and extract different compounds [18,20]. The most common extracts used in biological assays are ethanol, in different concentrations, methanol and water [18]. The seasonal variations in propolis composition are not significant and bees do not change its chemical composition in a specific geographic region because they visit essentially the same vegetal sources [18]. Many authors have studied the antifungal activity of propolis against C. albicans (Table 1) [13,17,21,31,32] and the ethanol extract has shown one of the best activities [13,20,31]. Furthermore, although flavonoid compounds have been considered responsible for the inhibitory effect on yeast, this effect could also be due to a different class of compounds [13]. The antimicrobial activity of propolis may occur through direct action against microorganisms and indirectly as well via stimulation of the immune system and further microorganism killing. The ultrastructural findings seen in scanning electron micrography suggested that the antifungal activity of propolis is due to changes in the cell wall leading to an increase in volume and cell membrane rupture [33]. Sforcin [18] states that propolis may activate macrophages, increasing their microbicidal activity. Among several biological activities described for propolis, antifungal and anti-inflammatory activities suggest its possible use in the local treatment of DS (Table 1) [9,34]. Despite the increasing use of propolis worldwide, only a few studies have been conducted to determine the therapeutic effect of propolis against this oral condition. Santos et al. [34] studied the topical therapeutic effect of ethanol extract of propolis on oral candidiasis associated with stomatitis caused by wearing dentures, and observed regression of lesions in all patients treated. Moreover, in another research, the authors evaluated
Table 1 Biological activity of propolis samples against Candida albicans. Authors
Propolis samples
Extract
Antifungal activity
Kujumgiev et al. [21]
Prudentopolis, Parana State, Brazil Pacajus, Ceara State, Brazil Limera, São Paulo State, Brazil Ribeirão Preto, São Paulo State, Brazil
Ethanolic extract 70%
In vitro
Ethanolic Ethanolic Ethanolic Ethanolic
In vitro
Sawaya et al. [13]
Silici et al. [31]
Santos et al. [34] Santos et al. [9]
Adana, South Anatolia, Turkey Kayseri, Central Anatolia, Turkey Artvin, North Anatolia, Turkey Minas Gerais State, Brazil Minas Gerais State, Brazil
extract extract extract extract
70% 50% 30% 80%
In vitro
Ethanolic extract 80% Ethanolic extract 90%
In vivo In vivo
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the clinical efficacy of an ethanol-free propolis gel formulation in patients diagnosed with DS. This propolis gel presented mucoadhesive properties and all patients showed complete remission of palatal edema and erythema after one week of treatment [9]. The results of the study of Ceschel et al. [27], who investigated a topical mucoadhesive gel containing propolis, showed that propolis is soluble in hydroxylic solvents such ethanol and propylene glycol. Ethanol has a very low viscosity and rapidly solubilizes propolis, but this solvent causes mucosal irritations and for this reason its use in formulations has been avoided. Propolis is relatively soluble in propylene glycol but with very low dissolution kinetics, perhaps due to the high viscosity of this solvent. Surfactants, such as polysorbate, significantly improve propolis solubility. For this reason, a polysorbate solution in propylene glycol has been chosen as a gel solvent. In order to obtain a mucoadhesive gel formulation, the polymer hydroxypropyl cellulose has been chosen because it shows the best gelling and mucoadhesive properties. Finally, the resultant product is obtained by dropping water to a minimum to formulate a sticky solution. This propolis gel formulation has been show to be an alternative topical choice for the treatment of DS [9]. Biological activities of others plants against C. albicans are summarized in Table 2. 2.2. Punica granatum Pomegranate (P. granatum) is a rich source of anthocyanins and other phenolic compounds that have strong antioxidant activity. The edible parts of pomegranate fruit (about 80% of total fruit weight) comprise 80% juice and 20% seed. Pomegranate fruit extract is a rich source of 2 types of polyphenolic compounds: anthocyanins, which give red color to the fruit and juice, and hydrolysable tannins, which account for 92% of the anti-oxidant activity of the whole fruit [35]. Pomegranate juice has many biological effects, some of which may have important clinical implications. Anti-atherogenic [36], anti-oxidant, anti-tumor [37] and virucidal [38] effects have been reported for P. granatum. In addition, the antimicrobial activity of this fruit has been widely investigated. The findings of several studies, including some relating to inhibition of adherence, suggest that oral bacteria and C. albicans are sensitive to the extract of P. granatum [39–41]. The action of tannins against yeasts can be established by a relationship between their molecular structure and
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their toxicity, astringent properties or other mechanisms still not well clarified. The effect of tannins on microbial metabolism can be measured by their action on membranes. They can cross the cell wall, composed of several polysaccharides and proteins, and bind to its surface [41]. In general, polyphenols certainly interfere in salivary proteins and some oral bacterial enzymes. They may affect microorganism membranes and disturb microorganism coaggregation [10]. Although P. granatum do not exhibit well established fungicidal or fungistatic activity, this therapeutic agent may inhibit yeast adherence by other mechanisms and can represent a new perspective in the combat and control of DS. Up to now, the P. granatum gel used in investigations against candidosis was prepared with the bark of fresh fruits. The basic gel consists of carbopol, water, triethanolamine and 0.5 ml of the raw extract, equivalent to 540 mg of the plant powder [10,41]. In the first clinical trial, patients with DS applied the gel on the lesions, and negativity of yeasts was observed in most subjects. Therefore, this P. granatum extract gel against candidosis-associated DS may be used as a topical antifungal agent for the treatment this disease [10]. In another study, the authors evaluated the antimicrobial effect of this phytotherapic gel on the adherence of C. albicans to glass. Adherence to glass observed in this study was similar to that occurring on prosthetic surfaces and this phytotherapeutic agent might be used to control the adherence of different microorganisms in the oral cavity [41]. 2.3. Streblus asper Streblus asper Lour (Moraceae) is a small tree, indigenous to tropical countries such as India, Sri Lanka, Malaysia, the Philippines and Thailand. It is also known as the tooth brush tree [42]. The compounds comprising S. asper include volatile oils. This ethnomedicinal plant is a rich source of cardiac glycosides, and asperoside, strebloside and mansoni are the few active compounds that have been isolated from this plant [43]. This medicinal plant is used for several pharmaceutical purposes. Different parts of S. asper have been found to exhibit cardiotonic, antifilarial, anticancer, antimicrobial, anti-allergic and antimalarial activities [43]. Among several others biological activities, its extract has been used for relief of fever, dysentery, toothache and gingivitis [44]. In addition, bactericidal activity was found in the 50% ethanol extract of its leaves [42]. In spite of its many beneficial
Table 2 Biological activity of plants against Candida albicans. Authors
Scientific name
Vasconcelos et al. [41]
Punica granatum Linn –
Taweechaisupapong et al. [6] Streblus asper Polaquini et al. [15] Han [16] Catalán et al. [2] (–) not informed.
Azadirachta indica Vitis vinifera Melaleuca alternifolia
Extract
Mechanisms of action
Astringent properties Cross the cell wall Disturb microorganism co-aggregation Ethanolic extract Reduce the ability to induce germ tube formation Changes in cell surface hydrophobicity Aqueous extract Changes in cell surface hydrophobicity Ethanolic extract Inhibition of fungal growth The Australian Tea Tree Oil Research Institute Ltd., Inhibitory to yeast growth Australia
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properties, 50% S. asper leaf ethanolic extract (SAE) [42] or at concentration ≤ 250 mg/ml [44] was shown to have no fungicidal activity against C. albicans. However, these sublethal concentrations of extract can block the adherence of Candida to human oral epithelial cells in vitro [44]. In another research, Taweechaisupapong et al. [6] observed that the exposure of C. albicans to sublethal concentrations of SAE resulted in a reduction in the ability of the yeasts to adhere to denture acrylic resin. Therefore, although S. asper does not have fungicidal property against C. albicans, it may possibly be a preventative for DS. Studies up to now have presented results related to the extracts only. Further studies are required to clarify the use of possible formulations incorporated into SAE. On the basis mechanisms of action, SAE reduced the ability to induce germ tube formation, inhibited Candida germination and reduced attachment to human epithelial cells [44]. Thus, the inhibition of germ tube formation by the SAE is important, since it is well known that germ tube and mycelial forms of C. albicans adhere more efficiently to host cells than do yeast form cells [45]. It is likely that the extract affect the Candida cell wall. Moreover, since cell surface hydrophobicity (CSH) is the major factor for Candida adherence to inert polymer [46], it is possible that SAE interferes with any changes in CSH, which would result in a shift in the free energy of interaction of the cell with the target surface, thereby reducing candidal adhesion [6]. 2.4. Azadirachta indica Azadirachta indica, commonly known as neem, is a tree native to the Indian subcontinent and Southeast Asia. The compounds isolated from this tree may be divided into two major classes: isoprenoids (diterpenoids and triterpenoids) and non-isoprenoids, which include proteins, amino acids, carbohydrates, sulfur compounds, polyphenolics such as flavonoids and others [47]. Neem has attracted worldwide attention in recent years, owing to its wide range of medicinal properties. Its constituents have been shown to have immunomodulatory, anti-inflammatory, antifungal, antibacterial, antiviral and anti-oxidant properties as their main biological activities [48]. In addition, the extract from A. indica is a powerful inhibiting agent against microorganisms that cause infectious diseases in the oral cavity, such as C. albicans. However, Neem aqueous extract does not seem to have a fungicidal effect against this fungus due to the low concentrations of the bioactive compounds, which may be increased when alcoholic extracts are involved [15]. Polaquini et al. [15] observed that C. albicans showed visible aggregation when incubated with Neem extract. The self-aggregation of yeast observed after the addition of the extract may be explained by the pronounced increase in hydrophobicity. Nevertheless, a decrease in adhesion capacity of cells to composite resin was also recorded. Thus, the study reinforces the possible anti-adhesive nature of the plant extract effect on the prevention of diseases of the oral cavity, although further clinical studies are needed before it is used. Moreover, the possibility of incorporating the extract into formulations for the treatment of candida-associated DS should also be studied.
2.5. Vitis vinifera Vitis vinifera (Common Grape Vine) is a species of Vitis bearing the fruit known as a grape and cultivated on every continent. Grape seeds are waste products of the winery and grape juice industry. These seeds contain lipids, proteins, carbohydrates, and 5–8% polyphenols, depending on the variety [49]. Polyphenols in grape seeds are mainly monomeric, oligomeric flavanols [50] and proanthocyanidins [51]. Grape seed extract (GSE) has been reported to exert protective effects against various forms of disease. GSE have demonstrated excellent free-radical scavenging [52]. In most cases, GSE activities are related to its anti-oxidant properties, mainly attributed to the phenolic compounds such as catechin and low-molecular proanthocyanidin [49]. Monomeric flavonols are directly implicated in the suppression of degenerative diseases such as cancer and atherosclerosis [50]. Furthermore, monomeric, phenolic and proanthocyanidin compounds act as antimutagenic and antiviral agents [51]. Nair et al. [53] believe that the immunomodulatory activities mediated by GSE may be due its product in which oligomers predominate. Several studies also have mentioned the antifungal activity of GSE against C. albicans [16,53–55]. Han [16] has shown that GSE enhances the resistance of mice against the disseminated candidiasis due to C. albicans. Moreover, the authors have observed that the polyphenolic compound epigallocatechin gallate (EGCG) present in GSE causes inhibition of C. albicans yeast cell growth. EGCG may function as anti-oxidants and cause oxidative-stress-related responses in yeast cells by the reactive oxygen species H2O2 [54]. Indeed, the grape seed contains many types of polyphenols, ranging from monomers to oligomers, which may induce differential effects on IFN-γ production and thus GSE selectively induces the production of Th1-derived cytokine IFN-γ [53]. In addition, IFN-γ enhances the NADPH oxidase activity involved in dendritic cell stimulation and increases the candida-killing activity in these cells [55]. Thus, these evidences suggest that GSE can be applied as a phytomedicine for the treatment of candidal infection. The grape seed has been studied only as an extract. The powdered seed material has been used to obtain 70% ethanol extracts, and the filtrate condensed and prepared in Dulbecco's Phosphate Buffered Saline (DPBS) solution [16]. Further studies with regard to formulations incorporated into GSE should be developed so that its use may be indicated as a topical antifungal agent against candidosis-associated DS. 2.6. Melaleuca alternifolia Tea tree oil (TTO) is the essential oil steam-distilled from the Australian native plant M. alternifolia. It is a complex mixture composed of approximately 100 monoterpene and sesquiterpene hydrocarbons and alcohols [56]. The oil is reported to have a range of medicinal properties, including antimicrobial, anti-inflammatory and analgesic effects [57,58]. TTO has been used as a natural topical antifungical agent due to its lipophylic nature, which facilitates skin penetration [2]. In this context, it has been clinically evaluated for the treatment of several superficial fungal infections, including onychomycosis [59], tinea [60] and refractory oral candidiasis [61].
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Hammer et al. [58] observed in vitro that the TTO reversibly inhibits the germ tube formation by C. albicans in the presence of, or pre-exposure to sub-inhibitory concentrations (0.25%) of TTO. These findings may be due to the effects of essential oils on cellular membrane properties and membrane-associated functions [62], including the inhibition of respiration [58]. Moreover, inhibition of respiration in yeast cells has been demonstrated by terpenic oil components [63], and consequent inhibition of germ tube formation by C. albicans by terpenes eugenol and vanillin [64]. Given the putative increased virulence of hyphae in comparison with blastoconidia, the inhibition of hyphal development is an advantageous characteristic for a therapeutic agent. TTO affects the ability of blastoconidia to germinate [58] and this may have therapeutic implication in the treatment of DS. This is consistent with Catalán et al. [2] who reported that in vitro 20% (vol/vol) of TTO mixed with either Coe-comfort or Fitt tissue conditioners has both inhibitory and fungicidal activity against C. albicans. In addition, the authors observed that patients treated with TTO mixed with Coe-Comfort showed decrease in palatal inflammation. These finding reinforce the idea that TTO could be used as an alternative therapy for DS resistant to traditional therapies. However, future research should still be performed to determine possible formulation issues related to the use of essential oil of M. alternifolia for the treatment of DS. 3. Conclusion Against this background, some phytomedicines can be suggested for the treatment of the candidal infection and consequently for DS. Nevertheless, further research is needed in order to clarify the antifungal mechanism of these extracts under different conditions. In addition, further clinical studies are required before they are used. Current opinion is that for their safe use, it is important to have standardized preparations of medicinal plant medications, which may be less toxic than many synthetic medicines. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.fitote.2009.12. 0036. References [1] Darwazeh AM, Al-Refai S, Al-Mojaiwel S. J Prosthet Dent 2001;86: 420–3. [2] Catalán A, Pacheco JG, Martínez A, Mondaca MA. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:327–32. [3] Pires FR, Santos EB, Bonan PR, De Almeida OP, Lopes MA. J Oral Rehabil 2002;29:1115–9. [4] Marchini L, Vieira PC, Bossan TP, Montenegro FL, Cunha VP. Gerodontology 2006;23:33–7. [5] Espinoza I, Rojas R, Aranda W, Gamonal J. J Oral Pathol Med 2003;32: 571–5. [6] Taweechaisupapong S, Klanrit P, Singhara S, Pitiphat W, Wongkham S. J Ethnopharmacol 2006;106:414–7. [7] Kulak Y, Kazazoglu E. J Oral Rehabil 1998;25:135–8. [8] Barnabé W, De Mendonça Neto T, Pimenta FC, Pegoraro LF, Scolaro LM. J Oral Rehabil 2004;31:453–9. [9] Santos VR, Gomes RT, Mesquita RA, Moura MDG, França EC, Aguiar EG, Naves MD, Abreu JAS, Abreu SRL. Phytother Res 2008;22:1544–7.
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