USE OF ESSENTIAL OILS IN ONYCHOMYCOSIS: AN INTEGRATIVE REVIEW

Objective: identify in the literature how essential oils are used in onychomycosis. Methods: integrative review with searches performed in the MEDLINE/PubMed, Web of Science, Cochrane, SCOPUS and BVS databases, with 13 studies analyzed. Results: the use of essential oils Melaleuca alternifolia, Lavandula angustifolia, Eucalyptus citriodora and Foeniculum vulgare are effective and bring benefits in the treatment of onychomycosis, as they inhibit the mycelial growth of the nail fungus. Therefore, health professionals involved in the care of people with onychomycosis must keep themselves updated on such treatment alternatives and, consequently, on improving the care provided to these patients. Conclusion: the antifungal efficacy of a variety of oils has been proven with different forms of presentation and possible associations. However, the level of evidence presented was low, which justifies the need for more robust studies on the subject. Objetivo: Identificar en la literatura se utilizan aceites esenciales en la onicomicosis. Métodos: Revisión integrativa, con búsquedas realizadas en las bases de datos MEDLINE / PubMed Web of Science, Cochrane, SCOPUS y VHL, donde se analizaron 13 estudios. Resultados: El uso de los aceites esenciales Melaleuca alternifolia, Lavandula angustifolia, Eucalyptus citriodora y Foeniculum vulgare resulta eficaz y aporta beneficios en el tratamiento de la onicomicosis ya que inhiben el crecimiento micelial del hongo ungueal. Así, los profesionales sanitarios implicados en la atención de las personas con onicomicosis onicomicosis deben mantenerse actualizados sobre dichas alternativas de tratamiento y, en consecuencia, sobre la mejora de la atención que se brinda a estos pacientes. Conclusión: La eficacia antifúngica de una variedad de aceites ha sido probada con diferentes formas de presentación y posibles asociaciones. Sin embargo, el nivel de evidencia presentado fue bajo, lo que justifica la


INTRODUCTION
Onychomycosis is a fungal infection that occurs on the nails and can affect the adjacent skin. It affects the nails of the feet more frequently than the nails of the hands and is characterized by discoloration of the nail, thickening of the nail plate and onycholysis. It is the most common nail pathology and represents about 90% of nail infections worldwide 1 .
The prevalence of the disease increases with a variety of risk factors, such as old age, abnormal nail morphology, immunodeficiency and genetic factors. Onychomycosis is a substantial health problem as it can have negative health consequences, such as pain, discomfort and physical impairment 2 .
National and international studies have found dermatophytes as the most commonly found etiologic agents in onychomycosis, being represented by the genera Trichophyton, Microsporum and Epidermophyton, followed by yeasts, represented mostly by the genus Candida, as well as by non-dermatophyte filamentous fungi, in which the Scopulariopsis, Fusarium and Aspergillus are the main genera [3][4][5] .
In more developed countries, the use of closed shoes, characteristic of large urban centers, creates an environment prone to onychomycosis by filamentous fungi. The humidity and the high temperature inside the shoes are conditions that favor the development of dermatophytes. On the other hand, walking barefoot in contact with the soil and vegetation is a habit that would favor onychomycosis by non-dermatophyte fungi (NDF) 6,7 . In view of the presentation of the pathology and its complexity, the use of essential oils in patients with onychomycosis is highlighted, in order to act in a beneficial way in its control. Essential oils are highly perfumed and volatile organic compounds obtained by extracting various parts of plants.
It usually has a watery and clear consistency, but can be solid at lower temperatures. They are soluble in alcohol, ether and other fatty compounds; insoluble in water and may have no color or present from light tones to darker and opaque.
Brazil occupies a recognized position in the production of essential oils, alongside India, China and Indonesia, which are on the list of the four largest world producers 8 .
Essential oils are called volatiles, because when they are in contact with air, at room temperature, they evaporate. Sparkling or ethereal are other names that can be found. However, the most used term is essential oil, as these represent the "essences" or odorous compounds of plants 9 . Terpenes, esters, ethers, alcohols, phenols, aldehydes, oxides, ketones, organic acids and other components detected as trace elements are the main constituents 10 .
Use of essential oils in onychomycosis: an integrative review When talking about the physiological an/or pharmacological action of essential oils, the effect is similar to that of a medicine or cosmetic, that is, according to the chemical substances found in the oil. These actions may be: analgesic, antibiotic, anti-inflammatory, antiseptic, antitoxic, astringent, bactericidal, depurative, diuretic, disinfectant, solvent, stimulant, among others 11 .
Thus, the realization of this study on the use of essential oils in onychomycosis aims to seek relevant data on the theme that has not yet been studied, thus showing the importance of the development of clinical research that serves as a subsidy for prevention and for the use of the multidisciplinary team with emphasis in specialized care by stomatherapy. Essential oils are considered materials that are easy to apply and access, characteristics that can provide differentiated care in the face of the needs of this public. In this context, this review aims to identify in the literature how essential oils are used in onychomycosis.

METHOD
Integrative literature review, guided in six phases: definition of the research question, sampling or search in the literature, extraction of data from included studies, evaluation of productions, interpretation of results and synthesis of knowledge or presentation of the review12. To elaborate the guiding question, the PICo strategy was used, defining: P = population: "original studies", I = interest: "essential oils" and Co = context: "onychomycosis". Therefore, the question in this study was: how are essential oils used in onychomycosis?
Primary source studies, without temporary delimitation, that dealt with the use of essential oils in the treatment of onychomycosis were included. Exclusion criteria were defined as studies published only as abstracts, theses, Observing the peculiarities and distinct characteristics of each database, systematic strategies were built using the advanced search. The controlled and non controlled descriptors, within each set of terms in the PICo strategy, were combined with the Boolean operator OR and then crossed with the Boolean operator AND, as shown in Table 1.
Initially, 58 productions were found, of which 20 were removed from the study due to duplication. After analyzing the titles and abstracts, 11 were excluded because they were not primary articles and 4 presented only the abstract available in the database. The reading of the full text to assess eligibility excluded 11 other articles for not answering the research question, and the final sample consisted of 13 articles. Fig. 1 describes the path taken for the identification, inclusion and exclusion of studies, according to the consulted base.
Data extraction was performed with the aid of a specific instrument, containing the following information: main author, year of publication, title, place and type of study, objective, intervention, main results and level of evidence (LE). For the LE analysis, the concepts proposed by Melnyk and Fineout-Overholt were adopted13:level I -evidence from systematic review or meta-analysis of all relevant randomized controlled clinical trials or from clinical guidelines based on systematic reviews of randomized controlled clinical trials; level II -evidence derived from at least one well-designed randomized controlled clinical trial; level III -evidence obtained from well-designed clinical trials without randomization; level IV -evidence from well-designed cohort and case-control studies; level V -evidence from systematic review of descriptive and qualitative studies; level VI -evidence derived from a single descriptive or qualitative study; and level VII -evidence from the opinion of authorities and/or reports from expert committees.

RESULTS
The results are shown in Table 2, according to the main author: year of publication, title, place and type of study, objective, intervention, main results and LE.
The year with the largest number of published articles was 2002 with 3 studies, followed by 2015 with 2 and the remaining years with 1 study only. It is noteworthy that the oldest study that works with the theme dates from 1994 and the most recent from 2016.
As for the language, the 13 articles were published in English. It is noteworthy that the most recent works were developed in Brazil, which also stood out in terms of location, being represented by 5 surveys, followed by the United States of America with 3 studies. Regarding LE, 11 studies are classified IV and 2 with LE II.
Melaleuca oil was highlighted over the other oils studied, as it is present in six articles. The studies presented data on efficacy, association, comparison, form of presentation and formulation.

Melaleuca alternifólia and Lavandula angustifolia
The results confirm that the synergistic action occurs between these two essential oils commonly used to effect antifungal activity. continue...

Melaleuca alternifolia
The in vitro activities of the commercial Melaleuca alternifolia essential oil, also called TTO, and chitosan were investigated against Candida albicans, both alone and in combination, to assess the potential of their synergistic action.

Melaleuca alternifolia
Nanocapsules containing M. alternifolia essential oil were the most effective in reducing the growth of T. rubrum. Another advantage of this system was the prevention of nail infection caused by T. rubrum in an in vitro onychomycosis model, demonstrating the potential of nanoencapsulation in the treatment of superficial mycoses.
continue... Establish the antifungal activity of some monoterpenes found in volatile oils (GOL, NOL, GAL, NAL and CIT) and investigate possible mechanisms of action for these substances.
Monoterpenos The antifungal activity of geraniol, nerol, citral, neral and geranial (monoterpenes) and terbinafine and anidulafungin (control drugs) against seven opportunistic pathogenic yeasts and four species of dermatophytes was evaluated by microdilution tests. Monoterpenes were more active against dermatophytes than against yeasts with 34.5 and 100.4 μg.ml -1 GMCI Ergosterol relating its mechanism of action to the destabilization of the cell membrane.
Rio de Janeiro, Brazil.

Cohort study; LE IV
Identify the main components of the essential oil of Baccharis trimera Less and investigate its antifungal activity in vitro against seven fungal strains that cause onychomycosis.

Baccharis trimera less
The essential oil has antifungal activity against filamentous fungi and can be used as an alternative for the treatment of onychomycosis. The essential oil of B. trimera has an antifungal effect against two of the three genera of filamentous fungi.

Protium heptaphyllum
There was considerable antifungal activity of the protium oil resin, inhibiting species of Candida, by the disk diffusion method, with halo diameter (Χ> 14mm), which cause a wide spectrum of superficial invasive infections and nail infections. Use of essential oils in onychomycosis: an integrative review

DISCUSSION
The articles included in this review bring studies that seek to prove the antifungal efficacy of essential oils 14,18 as well as its composition and mechanisms of action [15][16][17][19][20][21][22][23][24][25] . Thus, including analyzes of the association of substances, composition, comparison and different formulations against the main etiological agents of onychomycosis.
The oldest article in the present study and with the highest LE, it is a double-blind, multicenter, randomized and controlled clinical trial, which addresses the efficacy and tolerability of topical application of 1% clotrimazole solution (CL) compared to pure oil of Melaleuca alternifolia 100% (TT) for the treatment of onychomycosis.
Finding similar results with the two therapies at the end of the 6 months of the research, with curing of the culture (CL = 11%, TT = 18%) and partial or total resolution (CL = 61%, TT = 60%) according to evaluation clinic 14 .
Melaleuca alternifolia oil in different concentrations, proposed by the clinical trial, also reversibly inhibited the formation of germ tubes (FGT) in C. albicans in the highest concentrations of oil (0.25%). However, at lower concentrations (0.125%), FGT was specifically inhibited while growth continued through sprouting. These findings may be due to the effects on cell membranes and associated functions, including inhibition of breathing 15 .
In other studies, a cohort and a randomized controlled clinic, associations of components to the essential oil of Melaleuca alternifolia were presented, seeking knowledge about a supposed increased fungicidal effect. [17][18]20 .In one study, two essential oils, Melaleuca alternifolia and Lavandula angustifolia, were combined to inhibit Trichophyton rubrum, a dermatophyte fungal agent that colonizes the surface of human skin and is the main cause of "athlete's foot" and onychomycosis. On day 7, a proportion of 30% v/v lavender or 20% v/v of Melaleuca oil was used, resulting in 100% inhibition. On day 14, the minimum dilution to maintain 100% inhibition was 40% v/v lavender or 30% v/v Melaleuca oil. In the analysis of synergy of oils, the minimum dilution of mixtures of essential oils that give 100% inhibition was 10% v/v lavender with 20% v/v Melaleuca oil or 20% v/v lavender with 10% v/v Melaleuca oil. On day 14, the cultures that had been exposed to these mixtures also maintained 100% inhibition. Thus, confirming that the synergistic action occurs between these two essential oils commonly used in effecting antifungal activity 17 .
Another association tested in a clinical study was topical therapy with 5% Melaleuca alternifolia oil and 2% butenafine hydrochloride. This cream, in conjunction with debridement with a nail clipper, was considered safe, tolerable and significantly more effective than placebo (Melaleuca oil only) for curing toe nail onychomycosis.
Result evidenced after verifying 80% of cure in the group that used the association for 8 weeks, against no case of cure in the group that used the placebo. Raising the hypothesis that the time was not enough for healing in the group that used only Melaleuca oil, since this has proven efficacy by several studies 18 .
In the evaluation of the antifungal effect, in a cohort study, against Candida albicans of Melaleuca oil associated with chitosan, it was found that it did not significantly improve the activity of the oil, a finding that can be explained due to the longer time that the inhibitory concentrations of chitosan need to show your activity. Individually, Melaleuca oil inhibited C. albicans at 0.5% v/v and was able to kill yeast cells in 120 minutes at 1% and in 300 minutes between 0.5 and 0.25%. Regarding chitosan, 0.5 mg/mL was needed to inhibit the growth of Candida in a liquid environment, while 0.5 -2 mg/mL of chitosan was required 24 hours to kill them in the death kinetics test. bacterial (time-kill) 20 .  In a cohort study carried out in Brazil, positive results of monoterpenes, present in essential oils, were presented in the "Affinity Test with Ergosterol" and the other reports on the subject strongly suggest that the mechanism of action of this class of drugs is related to the ergosterol link and the subsequent destabilization of fungal cell membranes 23 . values of the oil ranged from 62.5 µg · mL −1 to > 1.000 µg · mL −1 , and the MFC values of the oil ranged from 125 µg · mL −1 to > 1.000µg · mL −1 . The analysis by electron microscopic scanning showed physical and morphological damage as changes in the fungi exposed to this oil, demonstrating the potential of Eucalyptus smithii essential oil as a natural therapeutic agent for the treatment of dermatophytosis 25 .
Against Candida species isolated from horticulturists with onychomycosis, by the method of disc-diffusion, the essential oil of the Protium heptaphyllum resin has antifungal activity. Important result being one of the main species causing onychomycosis. Demonstrating inhibition, even, with C. krusei, naturally resistant to the drug fluconazole, a similar situation occurred with the strain of C. parapsilosis 26 .
The results of the studies suggest evidence that essential oils are effective and beneficial in the treatment for onychomycosis. Therefore, health professionals involved in the care of patients with onychomycosis must keep up to date on such alternatives for the treatment of onychomycosis and, consequently, of improving the quality of life of these patients.
As a limitation for the elaboration of this integrative review, the presence of studies with low scientific evidence stands out, as well as few clinical studies on the topic discussed.

CONCLUSION
In view of the analyzed articles, it can be said that studies on essential oils present promising data, but these are mostly from preclinical studies, even though in the two included clinical trials the data have pointed to therapeutic efficacy.
The clinical studies presented show that essential oils, when compared to other therapies, proved to be as effective as conventional therapies, such as clotrimazole, terbinafine and ketoconazole.
However, most of the studies identified have a low level of evidence because they are pre-clinical studies, thus showing the need for the production of studies with experimental design, which can safely base the application in clinical practice, also aiming at contribution in the care of patients affected by this pathology.

DATA STATEMENT AVAILABILITY
Not applicable