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Brazilian Journal of Pharmaceutical Sciences

On-line version ISSN 2175-9790

Braz. J. Pharm. Sci. vol.52 no.2 São Paulo Apr./June 2016

http://dx.doi.org/10.1590/S1984-82502016000200001 

Reviews

Anti- Sporothrix spp. activity of medicinal plants

Stefanie Bressan Waller 1   *  

Isabel Martins Madrid 2  

Renata Osório de Faria 1  

Marlete Brum Cleff 3  

João Roberto Braga de Mello 4  

Mário Carlos Araújo Meireles 1  

1Departamento de Veterinária Preventiva, Faculdade de Veterinária, Universidade Federal de Pelotas, UFPEL, Pelotas/RS, Brasil

2Centro de Controle de Zoonoses, CCZ, Prefeitura Municipal de Pelotas, Pelotas-RS, Brasil

3Departamento de Clínicas Veterinária, Faculdade de Veterinária, Universidade Federal de Pelotas, UFPEL, Pelotas/RS, Brasil

4Departamento de Farmacologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, RS, Brasil.

ABSTRACT

Cases of sporotrichosis in humans and animals without satisfactory clinical response have increased, a warning sign of strains resistant to conventional antifungal agents. The urgent search for alternative therapies was an incentive for research on medicinal plants with anti-Sporothrix spp. properties. A bibliographic survey was performed based on scientific papers about in vitro and in vivo antifungal activity of essential oils and extracts of plants in differents solvents against the fungal of the Sporothrix schenckii complex. The study methodology consisted of a literature review in Google Scholar, Science Direct, Pubmed, Bireme and Springer link with papers from 1986 to 2015. We found 141 species of plants that were investigated, of which 100 species were concentrated in 39 botanical families that had confirmed anti-Sporothrix activity. Combretaceae, Asteraceae and Lamiaceae represented the botanical families with the greatest number of plants species with antifungal potential, using different methodologies. However, there are few studies with medicinal plants in experimental infection in animals that prove their activity in the treatment of sporotrichosis. It reinforces the need for further research related to standardization of in vitro methodologies and in vivo studies related to safety and to toxicity potential of these plants with anti-Sporothrix spp. activity.

Uniterms: Sporothrix schenckii complex; Antifungals; Combretaceae/pharmacognosy; Asteraceae/pharmacognosy; Lamiaceae/pharmacognosy; Medicinal plants/antifungal activity

RESUMO

Casos de esporotricose em humanos e animais sem resposta clínica satisfatória têm aumentado, sinal de alarme para o surgimento de cepas resistentes aos antifúngicos convencionais. A urgente busca por alternativas terapêuticas tem incentivado as pesquisas em plantas medicinais com atividade anti-Sporothrix spp. Um levantamento bibliográfico foi realizado com base em artigos científicos sobre a atividade antifúngica in vitro e in vivo de óleos essenciais e extratos de plantas preparados em diferentes solventes contra o complexo Sporothrix schenckii. A metodologia do estudo consistiu em uma revisão bibliográfica em Google Scholar, Science Direct, Pubmed, Bireme e Springer link com artigos desde 1986 até 2015. Foram encontradas 141 espécies de plantas já investigadas, das quais 100 espécies concentradas em 39 famílias botânicas apresentaram atividade anti-Sporothrix spp. confirmada. Combretaceae, Asteraceae e Lamiaceae representaram as famílias botânicas com maior número de espécies vegetais com potencial antifúngico, empregando diferentes metodologias. Entretanto, há poucos estudos com plantas medicinais em infecção experimental animal comprovando sua atividade no tratamento da esporotricose. Reforça-se a necessidade de mais pesquisas relacionadas à padronização de metodologias in vitro e a estudos in vivo relacionados à segurança e potencial tóxico dessas plantas com atividade anti-Sporothrix spp.

Unitermos: Sporothrix schenckii; Antifúngicos; Combretaceae/farmacognosia; Asteraceae/farmacognosia; Lamiaceae/farmacognosia; Plantas medicinais/atividade antifúngica

INTRODUCTION

Among the diseases with zoonotic potential, sporotrichosis is recognized as an emerging mycosis with worldwide occurrence that tends to increase exponentially in the number of cases in domestic animals and humans and is considered a neglected epidemic in the state of Rio de Janeiro, Brazil (Schubach, Barros, Wanke, 2008; Barros et al., 2010; Silva et al., 2012; Rodrigues et al., 2013). This disease is the most common subcutaneous mycosis in the Americas, especially in Brazil, Mexico, Colombia and Peru, and also occurs in South Africa, India and Japan (Carrada-Bravo, Olvera-Macías, 2013). The sources of environmental fungus infection include soil, decomposed vegetation, tree stems, and other elements. The infection may also occur through bites and scratches of cats that may carry Sporothrix spp. conidia and, through inoculation, transmit the fungal agent into the dermis (Larsson, 2011; Romeo, Criseo, 2013). Although the treatment with antifungal drugs is effective, in vitro studies acknowleded the emergence of strains of Sporothrix spp. resistant to antifungals (Meinerz et al., 2007; Marimon et al., 2008; Rodrigues et al., 2013; Stopiglia et al., 2014).

There is a continuing and urgent need to discover new antifungal compounds and to understand their mechanisms of action (Kontoyiannis, Lewis, 2002; Cleff et al., 2008; Gaitán et al. 2011). It is known that the use of plants and derivatives for medicinal purposes is an ancient practice used worldwide, primarily in Eastern cultures, and is utilized by up to 80% of the population of developing countries and has been increasingly used in the West, according to data from the World Health Organization in the 1990's (Veiga Jr., Pinto, 2005).

Faced with resistant cases of sporotrichosis, the search for alternative therapies in their treatment has increasingly been conducted by several international researchers, whose papers reveal the potential anti-Sporothrix spp. of certain medicinal plants (Rojas et al., 2003; Masoko, Picard, Eloff, 2007; Cleff et al., 2008; Suleiman et al., 2009; Johann et al., 2011; Joshi et al., 2011; Stopiglia et al., 2011). However, there is a lack of standardization of tests with medicinal plants and this makes the comparison of antifungal activity of the plants difficult. Thus, this review aimed for a new approach of sporotrichosis and grouped the studies in the medicinal plants with anti-Sporothrix spp. activity according to the methodology for antifungal evaluation. A bibliographic survey was performed based on scientific papers researched in Google Scholar, Science Direct, Pubmed, Bireme and Springer link and papers from 1986 to 2015 were evaluated.

SPOROTRICHOSIS AND ITS CONVENTIONAL THERAPY

Chronic or subacute, the clinical manifestations of sporotrichosis occur in dependence of the host immune status, commonly resulting in limited damage to the dermis, with or without involvement of the lymphatic system in humans and animals, which can produce subcutaneous nodules, and may also produce manifestations in the respiratory system, such as dyspnea, nasal discharge and sneezing (Schubach, Barros, Wanke, 2008; Barros et al., 2010; Madrid et al., 2012).

The conventional therapy for sporotrichosis includes the use of antifungal agents such as potassium iodide, itraconazole, ketoconazole, amphotericin B and terbinafine, among others, as well as the adoption of local thermal therapy and the surgical excision of the lesion (Meinerz et al., 2008; Gremião et al., 2009; Honse et al., 2010; Pereira et al., 2011; Gremião et al., 2011; Reis et al., 2012). The preferred antifungal therapy for cat and dogs with sporotrichosis has been itraconazole administered daily orally at the dose of 10 to 40 mg kg-1 for a minimum period of three months and up to one year with no apparent adverse effects (Madrid et al., 2010; Larsson, 2011; Rossi et al., 2013). However, poor clinical response has been observed in cats with sporotrichosis (Gremião et al., 2011).

The daily use of potassium iodide in capsules at dose of 2.5 to 20 mg kg-1 has provided clinical cure, although side effects may occur, as appetite loss and clinical signs of hepatotoxicity (Reis et al., 2012). The association of subcutaneous amphotericin B with oral itraconazole is also an alternative in cats with sporotrichosis refractory to itraconazole (Gremião et al., 2011). Furthermore, the association of itraconazole with (1-3) β-glucan promoted the case resolution after four weekly applications of glucan in a canine with refractory sporotrichosis to itraconazole by Sporothrix brasiliensis and it may be considered a promising alternative in cases of resistance to conventional therapy (Guterres et al., 2014). In humans, the recommended the daily dosage of 100 up to 400 mg kg-1 of itraconazole has been succesfully used in a study with 645 patients, which the recovery rate was 94.6% (Barros et al., 2010).

Experimental models in rats showed better activity of terbinafine (250 mg kg-1) compared to itraconazole (100 mg kg-1) in treatment of systemic sporotrichosis (Meinerz et al., 2008), but in the cutaneous sporotrichosis, terbinafine (20 e 30 mg kg-1) has shown little efficacy while itraconazole (10 mg kg-1) showed good results (Antunes et al., 2009). In human isolates of S. schenckii, S. brasiliensis and S. globosa, terbinafine had better in vitro antifungal activity, followed by ketoconazole and fluconazole (Stopiglia et al., 2014).

The therapeutic protocol adopted must be associated with clinical monitoring of the patient, especially in felines because they are sensitive to many medications (Nobre et al., 2002; Madrid et al., 2012). Toxic effects has been cited in cats and dogs treated with azoles, such as anorexia, emesis and hepatotoxic signs, as well as lethal cases in cats treated with saturated sodium solutions or 20% potassium iodide (Larsson, 2011).

The difficulties in obtaining therapeutical success can be associated with treatment time and the high cost of drugs that has been discouraging to the animals´ owners, who often abandon the therapy. These factors coupled with the indiscriminate use of antifungal drugs contributed to the problem of antifungal resistance (Schubach et al., 2004; Marimon et al., 2008; Rodrigues et al., 2013). Unfortunately, in vitro studies showed the emergence of Sporothrix spp. resistant to antifungals, including itraconazole, which is used as the preferred therapy in sporotrichosis (Marimon et al., 2008; Rodrigues et al., 2013; Stopiglia et al., 2014).

The difficulties observed in the therapeutical cure in human and animals show that the current situation calls for new therapeutic alternatives and/or new complements to conventional antifungal therapy. It is know that medicinal plants present antimicrobial properties which have been increasingly reported in international studies and it is expected that plant extracts have different target sites than used by currently available antimicrobials in being effective against drug-resistant microbial pathogens (Gibbons, 2003), including resistant strains of Sporothrix spp.

Currently, the agent of sporotrichosis has been reclassified and related to several species of Sporothrix schenckii complex, such as S. brasiliensis, S. globosa, S. mexicana, S. albicans, S. inflata, S. schenckii var. luriei and S. schenckii var. schenckii; which are identified only by molecular biology techniques (Marimon et al., 2007). However, the studies on medicinal plants found in this review were only conducted with isolates of S. schenckii because this agent was, at the time, the only species identified in cases of sporotrichosis, since the genre had not yet been classified as Sporothrix schenckii complex.

PLANTS WITH ANTI- SPOROTHRIX SPP. POTENTIAL

Among the first reports of the search of plants with possible antifungal activity against S. schenckii, Minami and Oliveira (1986) studied alcoholic extract at 30% of Bidens pilosa (Compositae), a plant distributed in America, Asia and Africa, and they found no inhibitory antifungal activity. Fortunately, studies in the years following detected satisfactory in vitro activity of other plant species tested in different extracts types, concentrations and methodologies (Sinha, Gulati, 1990; Apisariyakul, Vanittanakom, Buddhasukh, 1995; Verástegui et al., 1996; Saikia et al., 2001; Rojas et al., 2003; Masoko, Picard, Eloff, 2005; Luqman et al., 2007; Damián-Badillo et al., 2008).

According to the queried data, 141 species of plants have been subjected to in vitro tests against S. schenckii, and anti-Sporothrix spp. activity was conferred in 100 species belonging to 39 botanical families, in which were highlighted the families of Combretaceae (31% - 31/100) (Masoko, Picard, Eloff, 2005; 2007; Suleiman et al., 2009), Asteraceae (11% - 11/100) (Rojas et al., 2003; Damián-Badillo et al., 2008; Salomão et al., 2008; Stopiglia et al., 2011) and Lamiaceae (7% - 07/100) (Sinha, Gulati, 1990; Luqman et al., 2007; Fernández, 2005; Cleff et al., 2008; Couto et al., 2015), which have the largest number of species with confirmed activity of interest. From the in vitro studies revised, a total of 233 extract products showed anti-Sporothrix spp. activity. The botanical information according to the consulted references is described in Table I.

TABLE I Medicinal plants with confirmed anti-Sporothrix spp. activity and their taxonomical and anatomical identifications, extract types and the country where the study was conducted by the consulted references 

Botanical Family Plant Species Plant Parts Extract Country Reference
Agavaceae Agave lecheguilla Root E Mexico Verástegui et al.,1996; 2008
Leaves E Mexico Verastegui et al., 2008
Agavaceae Agave lophantha Leaves E Mexico Verastegui et al., 2008
Agavaceae Agave picta Leaves E Mexico Verastegui et al., 2008
Agavaceae Agave scabra Leaves E Mexico Verastegui et al., 2008
Anacardiaceae Schinus terebinthifolius Leaves, Stems Di, E, EA, He Brazil Johann et al., 2007
Anacardiaceae Loxostylis alata Leaves Ac, Aq, Bu, Ch, CT Di, He, Ch, M South Africa, Nigeria Suleiman et al., 2009; Suleiman, Naidoo, Eloff, 2012
Anacardiaceae Protorhus longifolia Leaves Ac, Di, He, M South Africa, Nigeria Suleiman et al., 2009
Apiaceae Cuminum cyminum Seed Aq, EO, Ha, M India Chaudhary, Husain, Ali, 2014
Araucariaceae Araucaria spp. Resin E Brazil Salomão et al., 2008
Asteraceae Artemisia ludoviciana Leaves, Root, Flowers Aq, EA, MC Mexico Damián-Badillo et al., 2008
Asteraceae Heliopsis longipes Leaves, Root, Flowers Aq, EA, MC Mexico Damián-Badillo et al., 2008
Asteraceae Tagetes lucida Leaves, Root, Flowers Aq, EA, MC Mexico Damián-Badillo et al., 2008
Asteraceae Baccharis dracunculifolia Resin E Brazil Salomão et al., 2008
Asteraceae Ophryosporus peruvianus Leaves, Stems E Peru Rojas et al., 2003
Asteraceae Senecio culcitioides Aerial Parts E Peru Rojas et al., 2003
Asteraceae Pterocaulon balansae Aerial Parts M Brazil Stopiglia et al., 2011
Asteraceae Pterocaulon cordobense Aerial Parts M Brazil Stopiglia et al., 2011
Asteraceae Pterocaulon lanatum Aerial Parts M Brazil Stopiglia et al., 2011
Asteraceae Pterocaulon lorentzii Aerial Parts M Brazil Stopiglia et al., 2011
Asteraceae Pterocaulon polystachyum Aerial Parts M Brazil Stopiglia et al., 2011
Burseraceae Commiphora harveyi Leaves Ac, Di, He, M South Africa, Nigeria Suleiman et al., 2009
Caesalpiniaceae Senna alata Leaves E Guatemala Fernández, 2005
Caesalpiniaceae Hymenaea courbaril Leaves E Guatemala Sánchez, 2009
Campanulaceae Lobelia pyramidalis Aerial Parts EO Índia Joshi et al., 2011
Chloranthaceae Hedyosmum mexicanum Leaves E Guatemala Castellanos, 2007
Clusiaseae Hypericum uliginosum Grass E Guatemala Fernández, 2005
Combretaceae Terminalia brachystemma Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2005
Combretaceae Terminalia gazensis Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2005
Combretaceae Terminalia mollis Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2005
Combretaceae Terminalia prunioides Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2005
Combretaceae Terminalia sambesiaca Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2005
Combretaceae Terminalia sericea Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2005; 2010b; Masoko et al., 2010a;
Combretaceae Combretum acutifolium Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum albopunctactum Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007; 2010b; Masoko et al., 2010a
Combretaceae Combretum apiculatum Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum bracteosum Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum caffrum Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum celastroides spp. celastroides Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum celastroides spp. orientale Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum collinum spp. suluense Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum collinum spp. taborense Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum edwardsii Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum erythrophyllum Leaves Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum hereroense Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum imberbe Leaves Di South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum kraussii Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum microphyllum Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum moggii Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum molle Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum mossambicense Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum nelsonii Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007; 2010b; Masoko et al., 2010a;
Combretaceae Combretum padoides Leaves Ac, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum paniculatum Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum petrophilum Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum woodii Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum zeyheri Leaves Ac, Di, He, M South Africa Masoko, Picard, Eloff, 2007
Combretaceae Combretum vendae Leaves Ac, Di, He, M South Africa, Nigeria Suleiman et al., 2009
Compositae Baccharis glutinosa Leaves E Mexico Verástegui et al.,1996
Cornaceae Curtisia dentata Leaves, Stems Ac, Di, He, M South Africa Shai et al., 2008
Euphorbiaceae Croton ruizianus Leaves, Stems E Peru Rojas et al., 2003
Fabaceae Glycyrrhiza glabra Root E, EA Índia Fatima et al., 2009
Fabaceae Diphysa robinioides Leaves E Guatemala Sánchez, 2009
Geraniaceae Perlagonium graveolens - EO Índia Singh et al., 2012
Hydrophyllaceae Wigandia urens Leaves, Stems E Peru Rojas et al., 2003
Kirkiaceae Kirkia wilmsii Leaves Ac, Di, He, M South Africa, Nigeria Suleiman et al., 2009
Labiateae Satureja macrostema Leaves, Root Aq, EA, MC Mexico Damián-Badillo et al., 2008
Lamiaceae Origanum vulgare Aerial Parts EO Brazil Cleff, 2008; Couto et al., 2015
Lamiaceae Salvia lavanduloides Leaves, Flowers E Guatemala Fernández, 2005
Lamiaceae Rosmarinus officinalis Leaves EO Índia Luqman et al., 2007
Lamiaceae Ocimum basilicum - EO Índia Sinha, Gulati, 1990
Lamiaceae Ocimum canum (americanum) - EO Índia Sinha, Gulati, 1990
Lamiaceae Ocimum gratissimum - EO Índia Sinha, Gulati, 1990
Lamiaceae Ocimum sanctum - EO Índia Sinha, Gulati, 1990
Lauraceae Cinnamomum zeylanicum Cortex He Mexico Márquez, 2010
Liliaceae Agapanthus africanus Root E India Singh et al., 2008
Meliaceae Khaya anthotheca Leaves Ac, Di, He, M South Africa, Nigeria Suleiman et al., 2009
Moraceae Dorstenia contrajerva Root E Guatemala Castellanos, 2007
Myristicaceae Iryanthera lancifolia Stems E Peru Rojas et al., 2003
Myrtaceae Eucalyptus camaldulensis Leaves M Mexico Márquez, 2010
Myrtaceae Eucalyptus citriodora - EO India Akhtar et al., 2014
Myrtaceae Psidium guajava Leaves Ac, He Mexico Márquez, 2010
Myrtaceae Syzygium aromaticum Sprouts He Mexico Márquez, 2010
Myrtaceae Psidium acutangulum Leaves E Peru Wen et al., 2011
Ochnaceae Ochna natalitia Leaves Ac, Di, He, M South Africa, Nigeria Suleiman et al., 2009
Onagraceae Oenothera multicaulis Aerial Parts, Root E Peru Rojas et al., 2003
Piperaceae Piper abutiloides Aerial Parts Ha Brazil Johann et al., 2009
Poaceae Cymbopogon flexuosus - EO Índia Saikia et al., 2001
Poaceae Cymbopogon martini - EO Índia Saikia et al., 2001
Poaceae Cymbopogon winterianus - EO Índia Saikia et al., 2001
Polygalaceae Polygala campestris Whole Plant Di Brazil Johann et al., 2011
Polygalaceae Polygala paniculata Whole Plant E Brazil Johann et al., 2011
Polygalaceae Polygala sabulosa Whole Plant Di, EA Brazil Johann et al., 2011
Polygonaceae Rumex acetosa Leaves, Stems, Flowers E Brazil Johann et al., 2007
Rosaceae Rubus urticaefolius Leaves, Stems, Flowers E, EA Brazil Johann et al., 2007
Smilacaceae Smilax domingensis Leaves, Stems, Root, Flowers E Guatemala Fernández, 2005
Solanaceae Cestrum auriculatum Leaves E Peru Rojas et al., 2003
Valerianaceae Valeriana prionophylla Root E Guatemala Fernández, 2005
Verbenaceae Lippia graveolens Leaves E, He Guatemala Fernández, 2005; Beteta, 2005
Zingiberaceae Curcuma longa Rhizomes EO Thailand Apisariyakul, Vanittanakom, Buddhasukh, 1995
Zygophyllaceae Larrea tridentata Leaves E Mexico Verástegui et al.,1996

Ac, acetone; Aq, aqueous; Bu, butanol; Di, dichloromethane; Ch, chloroform; CT, carbon tetrachloride; E, ethanol; EA, ethyl acetate; EO, essential oil; Ha, hydroalcoholic; He, hexane; M, methanol; MC, methanol, chloroform, - Not informed by consulted reference.

IN VITRO SUSCEPTIBILITY TESTS

In the studies reviewed, the methodology utilized for research on plants were agar diffusion (Apisariyakul et al., 1995; Saikia et al., 2001; Rojas et al., 2003; Luqman et al., 2007; Damián-Badillo et al., 2008; Verástegui et al., 2008; Fatima et al., 2009; Márquez, 2010; Joshi et al., 2011), broth microdilution technique (Sinha, Gulati, 1990; Verástegui et al., 1996; Johann et al., 2007; Luqman et al., 2007; Cleff et al., 2008; Fatima et al., 2009; Johann et al., 2009, 2011; Joshi et al., 2011), bioautographic assay (Betina, 1973; Johann et al., 2007; 2011), serial microdilution at 24 and 48 hours (Masoko, Picard, Eloff, 2005; 2007; Suleiman et al., 2009) and agar cup method (Salomão et al., 2008).

In the various methodologies utilized in the references, variation was observed in the values of concentration tested in extracts, making it difficult to compare the results and, thus, the designation of those plants with high, medium and low anti-Sporothrix spp. activity was not performed. According to Fennel et al. (2004), the lack of standardized methods for antimicrobial tests with natural products results in variations of minimum inhibitory concentration values. In addition, according to them, the factors that influence the outcome of antimicrobial activity of a plant are the technique applied, the strain of microorganism used, the origin of the plant and the time of its collection, the type of preparation and the amount of extract tested, among others.

Agar Diffusion

The anti-Sporothrix spp. activity of medicinal plants by agar diffusion test have been described and, for most authors, the studies focused on human isolates (Apisariyakul et al., 1995; Saikia et al., 2001; Rojas et al., 2003; Damián-Badillo et al., 2008; Luqman et al., 2008; Verástegui et al., 2008; Fatima et al., 2009; Márquez, 2010; Joshi et al., 2011; Wen et al., 2011), according to Table II.

TABLE II Results of agar diffusion test done in plants with antifungal activity against Sporothrix schenckii complex and its characteristics of solvent extract tested, botanical family, plant species and fungal strain origin according to reference that demonstrated values of inhibition zone 

Botanical Family Plant Species Solvent Extract Origin of Sporothrix spp. Inhibition Zone* Reference
Agavaceae Agave lecheguilla Ethanol Human 10 mm Verastegui et al., 2008
Agavaceae Agave lophantha Ethanol Human 10 mm Verastegui et al., 2008
Agavaceae Agave picta Ethanol Human 16 mm Verastegui et al., 2008
Agavaceae Agave scabra Ethanol Human 9 mm Verastegui et al., 2008
Asteraceae Artemisia ludoviciana Ethanol Unspecified 1to 1.99 cm Damián-Badillo et al., 2008
Asteraceae Artemisia ludoviciana Methanol Unspecified 1 to 1.99 cm Damián-Badillo et al., 2008
Asteraceae Heliopsis longipes Ethanol Unspecified 1 to 1.99 cm Damián-Badillo et al., 2008
Asteraceae Ophryosporus peruvianus Ethanol Human 13 mm Rojas et al., 2003
Asteraceae Senecio culcitioides Ethanol Human 15 mm Rojas et al., 2003
Asteraceae Tagetes lucida Methanol Unspecified 1 to 1.99 cm Damián-Badillo et al., 2008
Asteraceae Tagetes lucida Ethanol Unspecified 1 to 1.99 cm Damián-Badillo et al., 2008
Campanulaceae Lobelia pyramidalis Essential oil MTCC 1359 13 mm Joshi et al., 2011
Euphorbiaceae Croton ruizianus Ethanol Human 13 mm Rojas et al., 2003
Fabaceae Glycyrrhiza glabra Ethanol AIIMS 5 mm Fatima et al., 2009
Fabaceae Glycyrrhiza glabra Acetyl acetate AIIMS 7 mm Fatima et al., 2009
Hydrophyllaceae Wigandia urens Ethanol Human 13 mm Rojas et al., 2003
Labiateae Satureja macrostema Ethanol Unspecified 1 to 1.99 cm Damián-Badillo et al., 2008
Labiateae Satureja macrostema Methanol Unspecified 1 to 1.99 cm Damián-Badillo et al., 2008
Lamiaceae Rosmarinus officinalis Essential oil AIIMS < 5 mm Luqman et al., 2007
Lauraceae Cinnamomum zeylanicum Hexane Unspecified 14 mm Márquez, 2010
Myristicaceae Iryanthera lancifolia Ethanol Human 13 mm Rojas et al., 2003
Myrtaceae Eucalyptus camaldulensis Acetone Unspecified 12 mm Márquez, 2010
Myrtaceae Eucalyptus citriodora Essential oil MTCC 1359 6.67 to 27 mm Akhtar et al., 2014
Myrtaceae Psidium acutangulum Ethanol IHEM§15503 22 mm Wen et al., 2011
Myrtaceae Psidium guajava Methanol Unspecified 16 mm Márquez, 2010
Myrtaceae Syzygium aromaticum Hexane Unspecified 43 mm Márquez, 2010
Onagraceae Oenothera multicaulis Ethanol Human 15 to 19 mm Rojas et al., 2003
Poaceae Cymbopogon flexuosus Essential oil Human 35 mm Saikia et al., 2001
Poaceae Cymbopogon martini Essential oil Human 19 mm Saikia et al., 2001
Poaceae Cymbopogon winterianus Essential oil Human 12 mm Saikia et al., 2001
Solanaceae Cestrum auriculatum Ethanol Human 25 mm Rojas et al., 2003
Zingiberaceae Curcuma longa Essential oil Human 3 mm Apisariyakul, 1995

*The resuls were described according authors reference and only species plants with results of inhibition zone were considered; Microbial Type Culture Collection and Gene Bank (Chandigarh, India); All India Institute of Medical Sciences (New Delhi, India); §Instutute of Hygiene and Epidemiology-Mycology Laboratory (Brussels, Belgium).

An Agar diffusion test consists of defying a microorganism against a biologically active substance in a solid medium culture, in which the absense of microbial growth is related to the size of the halo formed, demonstrating sensitivity of the strain to the extract (Pinto, Kaneko, Ohara, 2003). Considered one of the simplest and most trusted methods of sensitivity, this method is advantageous because of its ease of implementation and interpretation of results, as well as its use of inexpensive reagents and antibiotics without requiring special equipment. However, there is a deficiency of mechanization or automation to this method (CLSI, 2007). In regards to plant extracts, the difficulties with the test are the diffusion of the extract in the culture medium and pH of the substances used (Ostrosky et al., 2008), as well as the presence of contaminants such as heavy metals, drugs and other medicinal plants (Veiga Jr., Pinto, 2005).

In this methodology, methanol-chloroformic and ethyl acetate extracts of Satureja macrostema (Labiateae) and Tagetes lucida, Artemisia ludoviciana and Heliopsis longipes (Asteraceae) gave growth inhibition of S. schenckii in the zone ranging from 1.0 to 1.99 cm (Damián-Badillo et al., 2008). Better results were observed in 10% ethanolic extract of Agave lecheguilla, A. picta, A. scabra and A. lophantha (Agavae) between 9.0 and 16 mm at concentrations of 4.0 to 6.0 mg mL-1 (Verástegui et al., 2008). Popularly known as licorice, ethanolic extract from the roots of Glycyrrhiza glabra (Fabaceae) also inhibited the growth of S. schenckii at 5 mm diameter, as well as the active constituent of this plant - glabridin - and the ethyl acetate fraction of root with 6 and 7 mm, respectively (Fatima et al., 2009).

In traditional Peruvian medicine, a study with 36 ethanolic extracts of 24 plants from Asteraceae family showed the inhibition of S. schenckii to Croton ruizianus, Iryanthera lancifolia, Oenothera multicaulis, Ophryosporus peruvianus, Senecio culcitioides and Wigandia urens that promoted halo of growth inhibition of 13 to 19 mm and the best anti-Sporothrix spp. activity was related to Cestrum auriculatum with halo of 25 mm, including against strains with no susceptibility to amphotericin B and fluconazole, indicating the importance of the search for new compounds for resistant isolates (Rojas et al., 2003).

In another similar study, ethanolic extracts of Calycophyllum spruceanum (Rubiaceae), Spondia mombin (Anacardiaceae) and Thevetia peruviana (Apocynaceae) did not show anti-Sporothrix spp. activity, but leaves of Psidium acutangulum (Myrtaceae) inhibited S. schenckii with an halo of 22 mm and the active chemical composition "3'-formil-2',4',6'-trihidroxidihidrochalcone" was individually tested against strains resistants to amphotericin B and fluconazole by broth microdilution technique and showed MIC of 32 µg ml-1, being considered promising for therapeutic alternatives in sporotrichosis (Wen et al., 2011).

Popularly known as clove, extracts of hexane and acetone at 20% of Syzygium aromaticum (Myrtaceae) had greater anti-Sporothrix spp. activity with inhibition growth of 28 mm to 43 mm in the disc diffusion method on agar and the extracts of Cinnamomum zeylanicum (Lauraceae), Eucalyptus camaldulensis and Psidium guajava (Myrtaceae), popularly known as cinnamom, eucalyptus and guava, respectively, that inhibited S. schenkii in zones of 10 to 23 mm, but the most of the methanolic extracts of these tested plants did not show antifungal activity (Márquez, 2010). Still in Myrtaceae family, the ointment formulation of Eucalyptus citriodora Hook at 2% was more pronounced against S. schenckii with zone of growth inhibition of 27 mm, but cream formulation with essential oil and the proper essential oil of this plant had also fungistatic activity between 6.67 to 19.67 mm through agar disc diffusion (Akhtar et al., 2014).

In another study, Cymbogon winterianus (Poaceae) essential oil constituted a potential antifungal product (Pereira et al., 2011). S. schenckii was inhibited in the growth zone of 12 mm at dilution of 1/800 for C. winterianus, known as citronella, while C. martini and C. flexuosus inhibited with 19 mm and 35 mm, respectively, at dilution of 1/1600 (Saikia et al., 2001). In the Ocimum genus (Lamiaceae), the essential oils of O. sanctum, O. canum (O. americanum) and O. gratissimum was conferred activity between 8 and 14 mm of diameter (Sinha, Gulati, 1990). In other botanical species, S. schenckii has been inhibited by Lobelia pyramidalis (Campanulaceae), known as lobelia, with 13 mm of diameter (Joshi et al., 2011); Curcuma longa (Zingiberaceae), known as turmeric, with 3 mm (Apisariyakul et al., 1995), and Rosmarinus officinalis (Lamiaceae), known as rosemary, with 2.5 mm (Luqman et al., 2007). In commercially-available natural products from Perlagonium graveolens (Geraniaceae), Singh et al. (2012) showed that the compounds of terpineol and geranium oil had antifungal activity, while geraniol, phenyl ethyl alcohol and citronella acetate had not shown satisfactory activity.

In the methodology adapted by Brancato and Golding (1953), Beteta (2005) tested aqueous extracts and portions extracted with hexane, chloroform and ethyl acetate derived from the leaves of Lippia graveolens (Verbenaceae) and the flowers of Bourreria huanita (Boraginaceae) and showed that the antifungal activity was conferred only to L. graveolens whose hexanic fraction inhibited the yeast and filamentous phases when tested at a concentration of 0.5 mg mL-1, while the ethanolic fraction inhibited only the filamentous phase at 0.25 mg ml-1.

Ethanolic extracts of seeds of Phasoelus lunatus (Fabaceae) and leaves of Cassia grandis (Fabaceae), Diphysa robinioides (Fabaceae), Hymenaea courbaril (Caesalpiniaceae), Phasoelus vulgaris (Fabaceae), Senna occidentalis (Fabaceae) and Vicia faba (Fabaceae) were already tested and proved no activity against the yeast phase, but the filamentous phase showed sensitivity only to extracts of H. courbaril and D. robinioides tested at the concentration of 1 mg mL-1 and the MIC value of 0.5 mg mL-1 and 1 mg mL-1, respectively (Sánchez, 2009).

In another study, yeast and filamentous phases of S. schenckii were inhibited by the ethanolic extracts from roots of Dorstenia contrajerva (Moraceae) and leaves of Hedyosmum mexicanum (Chloranthaceae), being the mycelial phase inhibited at MIC of 0.1 mg mL-1 and 0.05 mg mL-1, respectively, but the yeast phase was only inhibited by H. mexicanum at MIC of 0.1 mg mL-1, however, the extracts from leaves of Baccharis triversis (Asteraceae), Lippia chiapasensis (Verbenaceae) and Ocimum micranthum (Lamiaceae) and the roots of Petiveria alliaceae (Phytolaccaceae) did not have activity against S. schenckii at maximum concentration of 0.2 mg mL-1 for both fungal phases (Castellanos, 2007). According to these authors, the plants that did not show satisfactory activity may have active chemical compounds in other botanical portions or when tested in higher concentrations, which does not rule out the possibility of possessing potential antifungal activity.

In ethanolic extracts from twelve plants native to Guatemala at the concentration of 1 mg mL-1 using agar diffusion adapted by Brancato and Golding (1953), the extracts of Hypericum uliginosum (Clusiaseae), Smilax domingensis (Smilacaceae), Salvia lavanduloides (Lamiaceae) and Senna alata (Caesalpiniaceae) inhibited S. schenckii in the yeast phase, while only the extracts of Lippia graveolens (Verbenaceae) and Valeriana prionophylla (Valerianaceae) showed activity for both phases of this dimorphic fungus. The other tested plants - Cornutia pyramidata (Verbenaceae), Quercus crispifolia (Fagaceae), Solanum americanum (Solanaceae), Sterculia apetala (Malvaceae), Tabebuia rosea (Bignoniaceae) and Tithonia diversifolia (Asteraceae) - did not exhibit activity against S. schenckii (Fernández, 2005).

According to Fernández (2005), the yeast phase would be more susceptible to the extracts for the lesser amount of ergosterol present in the membrane cell at this phase, leading to a greater susceptibility to permeability changes, as well as by the biosynthesis of ergosterol inhibition and other steroids by the active compounds present in the extracts. Another hypothesis of the antifungal mechanism would be the inhibition of its triglycerides and phospholipids biosynthesis or the inhibition of oxidative and peroxidative enzymatic activity that results in accumulation of toxic concentrations of hydrogen peroxide and leads to deterioration of subcellular organs and cell necrosis.

Broth Microdilution Method

Plants from different botanical families presented anti-Sporothrix spp. activity through tests of broth microdilution in standard strains isolated from humans and felines (Verástegui et al., 1996; Johann et al., 2007; Luqman et al., 2007; Cleff et al., 2008; Fatima et al., 2009; Johann et al., 2011; Joshi et al., 2011; Stopiglia et al., 2011). This method is based on the proportion of microbial growth in liquid medium challenged with the concentration of the measured substance using a 96-well microplate (CLSI, 2002; Pinto et al., 2003). Among the main advantages cited of this quantitative test are savings in space and reagents, generation of quantitative results through values of minimum inhibitory concentration and the use of pre-fabricated microdilution plates (CLSI, 2002). However, the cost of microdilution plates is a disadvantage, because the realization of a large number of antifungal tests may elevate costs (CLSI, 2002). Furthermore, Eloff (1998) observed compounds precipitation in some plants extracts and interference in the analysis by the high concentration of chlorophyll. In spite of these factors, this method is still considered advantageous for its high sensitivity and reproducibility in relation to other techniques (Eloff, 1998). The results of plants with anti-Sporothrix spp. activity confirmed by broth microdilution technique, as well as their botanical information are displayed in Table III.

TABLE III Results of microdilution test of plants species with activy against strains of Sporothrix schenckii complex and their different values of minimal inhibitory concentration according to references and solvent extract with action 

Botanical Family Plant Species Solvent Extract Origin of Sporothrix spp. Minimal Inhibitory Concentration Reference
Agavaceae Agave lecheguilla Ethanol Human 5.0 mg mL-1 Verástegui et al.,1996
Anacardiaceae Schinus terebinthifolius Ethanol, Hexane ATCC 22019 15 μg mL-1 Johann et al., 2007
Asteraceae Pterocaulon balansae Methanol Human 625 μg mL-1 Stopiglia et al., 2011
Asteraceae Pterocaulon cordobense Methanol Human 625 μg mL-1 Stopiglia et al., 2011
Asteraceae Pterocaulon lanatum Methanol Human 625 μg mL-1 Stopiglia et al., 2011
Asteraceae Pterocaulon lorentzii Methanol Human 625 μg mL-1 Stopiglia et al., 2011
Asteraceae Pterocaulon polystachyum Methanol Human 156 μg mL-1 Stopiglia et al., 2011
Campanulaceae Lobelia pyramidalis Essential oil MTCC 1359 6.25 mg mL-1 Joshi et al., 2011
Compositae Baccharis glutinosa Ethanol Human 12 mg mL-1 Verástegui et al.,1996
Fabaceae Glycyrrhiza glabra Ethanol AIIMS 1 mg mL-1 Fatima et al., 2009
Lamiaceae Origanum vulgare Essential oil Human; Feline 250 μL mL-1 Cleff et al., 2008
Lamiaceae Origanum vulgare Essential oil Human; ATCC 1099-18; ATCC 5110; IPEC* 15383; IPEC 17943 216 to 1735 μg mL-1 Couto et al., 2015
Lamiaceae Rosmarinus officinalis Essential oil AIIMS 11 mg mL-1 Luqman et al., 2007
Piperaceae Piper abutiloides Hydroalcoholic ATCC 20679 125 μg mL-1 Johann et al., 2009
Polygalaceae Polygala campestris Dichloromethane ATCC 20679 500 μg mL-1 Johann et al., 2011
Polygalaceae Polygala paniculata Ethanol ATCC 20679 1000 μg mL-1 Johann et al., 2011
Polygalaceae Polygala sabulosa Acetyl acetate ATCC 20679 30 μg mL-1 Johann et al., 2011
Polygonaceae Rumex acetosa Ethanol ATCC 22019 1000 μg mL-1 Johann et al., 2007
Rosaceae Rubus urticaefolius Acetyl acetate, Ethanol ATCC 22019 125 μg mL-1 Johann et al., 2007
Zygophyllaceae Larrea tridentata Ethanol Human 16 mg mL-1 Verástegui et al.,1996

American Type Culture Collection (Manassas, VA, USA); Microbial Type Culture Collection and Gene Bank (Chandigarh, India); *Instituto de Pesquisa Clínica Evandro Chagas (Rio de Janeiro, Brazil); All India Institute of Medical Sciences (New Delhi, India).

Lamiaceae family is known with potential antifungal for controlling the growth of pathogenic fungi and the occurrence of mycosis (Souza et al., 2010). Rosemary oil (Rosmarinus officinalis) showed in vitro activity against S. schenckii at concentration of 11 mg mL-1 (Luqman et al., 2007), as well oregano oil (Origanum vulgare), that inhibited S. schenckii concentrations between 250 to 500 μL mL-1 (Cleff et al., 2008; 2010). In S. schenckii and S. brasiliensis,Couto et al. (2015) showed the antifungal potential of oregano oil, as well as in its major compound (γ-terpinene), which caused morphological alterations in hyphae and reduced the adhered conidia numbers.

From the plants used in traditional medicine in Brazil, Johann et al. (2011) exhibited that ethanolic and ethyl acetate extracts of Rubus urticaefolius (Rosaceae) inhibited the fungal growth at the concentration of 125 μg mL-1, while Rumex acetosa (Polygonaceae) demonstrated activity at 1000 μg mL-1. The same activity was observed in the essential oil of Lobelia pyramidalis (Campanulaceae), which inhibited the fungal growth at MIC of 6.25 mg mL-1 (Joshi et al., 2011). Fatima et al. (2009) showed greater activity of ethanolic and hexanic extracts of Schinus terebinthifolius (Anacardiaceae) at 15 μg ml-1, as well as the ethanolic extracts at 15% from roots of Glycyrriza glabra (Fabaceae) at 1 mg mL-1 and glabridin and ethyl acetate fraction at 0.25 μg mL-1. Other plants were tested on S. schenckii, such as Piper regnelii (Piperaceae), Herissantia crispa (Malvaceae), Baccharis dracunculifolia (Asteraceae), Inga dulcis (Leguminosae) and Alternanthera brasiliana (Amaranthaceae) and did not show antifungal activity (Johann et al., 2007). In the Chihuahuan region (encompassing parts of Northern Mexico and the Southwestern United States), fungistatic activity was observed in the ethanolic extract at 80% of the leaves from Baccharis glutinosa (Compositae) and Larrea tridentata (Zygophyllaceae) and roots of Agave lecheguilla (Agavaceae) at MIC of 12, 16 and 5 mg mL-1, respectively (Verástegui et al., 1996).

In the Piperaceae family, Piper abutiloides presented MIC value of 125 μg mL-1 when tested in form of hydroalcoholic extract at 80%, but hexane, dichloromethane, ethyl acetate and aqueous extractions did not show antifungal activity at the maximum tested concentration of 1000 μg mL-1 (Johann et al., 2009). In the extract with antifungal activity, these authors isolated the compounds pseudodillapiol, eupomatenoid-6 and conocarpan, which provided fungistatic activity at MIC of 12.5 μg spot-1, 25 μg spot-1 and 50 μg spot-1 respectivelly, when individually tested against S. schenckii.

In the Polygala genus (Polygalaceae family), the ethyl acetate and dichloromethane of P. sabulosa had the better activity at MIC of 30 μg mL-1 and 250 μg mL-1, respectively, and dichloromethanic and ethanolic extracts of P. campestris, P. sabulosa and P. paniculata has activity between 500 to 1000 μg mL-1, but no activity was observed in extracts from P. cyparissias. The authors isolated the compounds "prenyloxycoumarin" and "1,2,3,4,5,6-hexanehexol" from P. sabulosa and these showed activity in the MIC value of 125 μg mL-1 and 250 μg mL-1, respectively (Johann et al., 2011).

Stopiglia et al. (2011) demonstrated in vitro efficacy of plants from the Pterocaulon genus (Asteraceae family) against 24 strains of S. schenckii, and the methanolic extract at 10% of P. polystachyum, P. lorentzii, P. lanatum, P. cordobense and P. balansae had inhibitory and fungicidal activity. Of these, the extract of P. polystachyum showed greater results with MIC ranged of 156 to 312 μg mL-1 and MFC varied between 312 to 1250 μg mL-1.

A variation of the broth microdilution technique, the Serial Microdilution Method is performed through the confirmation of the MIC value by the use of p-iodonitrotetrazolium violet (INT) in each well-test as a fungal growth indicator, indicated by reduction of the red color of INT formazan and evaluated within a period of 24 to 48 hours of incubation (Eloff, 1998; Masoko, Picard, Eloff, 2005). According to Table IV, acetonic, hexanic, dichloromethanic and methanolic extracts from leaves of six native species of trees in South Africa, belonging to the genus Terminalia (Combretaceae family) showed high activity in the MIC values of 0.02 to 0.64 mg mL-1 (Masoko, Picard, Eloff, 2005), as well as extracts from 24 plants of Combretum genus (Combretaceae) (Masoko, Picard, Eloff, 2007).

TABLE IV Results of Minimal Inhibitory Concentration (MIC) in the serial microdilution dilution method in different extracts of medicinal plants with activity against Sporothrix spp. in the period of 24 hours 

Botanical Family Plant Species Solvent Extract Origin of Sporothrix spp. MIC at 24 hours* Reference
Anacardiaceae Loxostylis alata Acetone Unspecified 0.04 mg mL-1 Suleiman et al., 2009
Methanol, Butano, Hexane, Chloroform, Carbon Tetrachloride, Water Unspecified 0.2 to 1.88 mg mL-1 Suleiman et al., 2012
Protorhus longifolia Dichloromethane Unspecified 0.84 mg mL-1 Suleiman et al., 2009
Burseraceae Commiphora harveyi Acetone Unspecified 0.31 mg mL-1 Suleiman et al., 2009
Combretaceae Combretum acutifolium; C. albopunctactum; C. apiculatum; C. edwardsii; C. hereroense; C. moggi; C. nelsonii; C. zeyheri Acetone Equine 0.02 to 0.04 mg mL-1 Masoko, Picard, Eloff, 2007
C. apiculatum; C. edwardsii; C. moggi; C. molle; C. mossambicense; C. petrophilum Methanol Equine 0.02 to 0.08 mg mL-1 Masoko, Picard, Eloff, 2007
C. apiculatum; C. microphyllum; C. mossambicense; C. paniculatum Dichloromethane Equine 0.02 to 0.04 mg mL-1 Masoko, Picard, Eloff, 2007
C. bracteosum; C. hereroense; C. mossambicense Hexane Equine 0.02 to 0.04 mg mL-1 Masoko, Picard, Eloff, 2007
C. celastroides spp. orientale; C. collinum spp. suluense; C. woodii Acetone Equine 0.08 mg mL-1 Masoko, Picard, Eloff, 2007
C. caffrum Methanol Equine 0.32 mg mL-1 Masoko, Picard, Eloff, 2007
C. celastroides spp. celastroides Methanol Equine 0.16 mg mL-1 Masoko, Picard, Eloff, 2007
C. collinum spp. taborense; C. kraussii Hexane, Dichloromethane Equine 0.16 mg mL-1 Masoko, Picard, Eloff, 2007
Combretum erythrophyllum Hexane Equine 0.32 mg mL-1 Masoko, Picard, Eloff, 2007
Combretum imberbe Dichloromethane Equine 0.32 mg mL-1 Masoko, Picard, Eloff, 2007
Combretum padoides Acetone Equine 0.32 mg mL-1 Masoko, Picard, Eloff, 2007
Combretum vendae Hexane Unspecified 0.13 mg mL-1 Suleiman et al., 2009
Terminalia brachystemma; T. mollis Dichloromethane Equine 0.02 mg mL-1 Masoko, Picard, Eloff, 2005
Terminalia gazensis; T. prunioides; T. sambesiaca Acetone Equine 0.02 to 0.08 mg mL-1 Masoko, Picard, Eloff, 2005
Terminalia prunioides Hexane Equine 0.04 mg mL-1 Masoko, Picard, Eloff, 2005
Combretaceae Terminalia sericea Methanol Equine 0.02 mg mL-1 Masoko, Picard, Eloff, 2005
Kirkiaceae Kirkia wilmsii Acetone Unspecified 0.26 mg mL-1 Suleiman et al., 2009
Meliaceae Khaya anthotheca Acetone Unspecified 0.11 mg mL-1 Suleiman et al., 2009
Ochnaceae Ochna natalitia Hexane Unspecified 0.08 mg mL-1 Suleiman et al., 2009

* The extrats types of considered plants were those with minimum values of inhibitory concentration at 24 hours.

Suleiman et al. (2009) showed the anti-Sporothrix spp. activity of different extracts from leaves of native species trees of South Africa: Combretum vendae (Combretaceae), Commiphora harveyi (Burseraceae), Khaya anthotheca (Meliaceae), Kirkia wilmsii (Kirkiaceae), Loxostylis alata (Anacardiaceae), Ochna natalitia (Ochnaceae) and Protorhus longifolia (Anacardiaceae). In different extracts at 10% of L. alata, acetonic extract of L. alata exhibited better antifungal activity in MIC of 0.04 mg mL-1 in 24 hours and 0.08 mg mL-1 in 48 hours (Suleiman et al., 2009) and other fractions of the L. alata had synergistic activity against Sporothrix spp. in the MIC of 0.2 to 1.88 mg mL-1 (Suleiman et al., 2012). These activities can be explained by the lupeol compound, which showed anti-Sporothrix spp. activity when individually tested at the MIC values of 57 μg mL-1 (Suleiman et al., 2013). Lupeol isolated from leaves and stem barks of Curtisia dentata B. (Cornaceae) showed higher activity (12 μg mL-1) when compared with betulinic acid, ursolic acid and 2-α-hydroxy ursolic acid isolated, that had also activity between 16 to 32 μg mL-1 (Shai et al., 2008).

In another study, the ethanolic extract of the rhizomes of Agapanthus africanus L. (Liliaceae) had activity against Sporothrix spp. with MIC value of 250 μg mL-1, and the compound saponin was isolated from this extract and was responsible for antifungal activity in MIC of 15.6 μg mL-1 (Singh et al., 2008).

Bioautographic Assay

Many researchers carry out bioautographic assay to detect new or unidentified compounds in plants of interest, in order to pursue and deepen the studies in cases of confirmed antimicrobial action (Betina, 1973). This test is based on assessing the inhibition zone afforded by the extract of interest, through the addition of this extract in silica gel plates and further immersion in a fungal suspension and addition of p-iodonitrotetrazolium violet (Rahalison et al., 1993). Among eight plants popularly used in traditional Brazilian medicine, Johann et al. (2007) measured the MIC values by broth microdilution technique only of six plants of different extracts, because those were effective against a several number of pathogens tested by bioautographic assay and the ethanolic extract of leaves from S. terebinthifolius (Anacardiaceae) showed better activity against S. schenckii at 15 μg mL-1.

In plants from Polygala genus, five species presented activity in the bioautographic assay and were submitted to broth microdilution test, demonstrating that ethanolic extract of P. paniculata (1000 μg mL-1) and the fractions of dichloromethane and ethyl acetate of P. sabulosa (250 μg mL-1and 30 μg mL-1, respectively) showed good antifungal activity against S. schenckii (Johann et al., 2011).

Agar Cup Method

Brazilian propolis produced by bees that collected pollen from Baccharis dracunculifolia (Asteraceae) and araucaria (Araucaria spp. - Araucariaceae) showed antifungal activity in the 30% ethanolic extract at the concentration of 16 to 2.0 mg mL-1 by the agar cup method, in which the antifungal activity is measured by inhibition zone diameter. The inhibitory action of both plants occurred when tested individually and jointly against S. schenckii, whose inhibition diameter ranged between 16 to 24 mm and the lowest concentration tested (2 mg mL-1) of B. dracunculifolia was able to inhibit the fungal growth up to 19 mm diameter (Salomão et al., 2008).

The small annual herb Cuminim cyminum L. (Apiaceae), popularly known as cumin, is the second most popular spice in the world, after black pepper, and showed activity against S. schenckii in the zone of inhibition of 18 mm to essential oil, 12 mm to methanol extract and 0.3 mm to hydroalcoholic extract, but aqueous extract of this plant did not show anti-Sporothrix spp. activity when the products where tested at concentration of 0.5 mg mL-1 (Chaudhary, Husain, Ali, 2014).

IN VIVO STUDIES

In vivo studies with aqueous creams containing 20% of acetone extracts (2 g of extract in 10 g of cream) from the leaves of different species of Combretaceae were evaluated in experimental cutaneous sporotrichosis and showed wound-healing properties when administered topically three times per week in rats Wistar. The preparations of leaves from Combretum imberbe, C. nelsonii, C. albopunctatum and Terminalia sericea (Combretaceae) have produced reversal of lesions in 15 days, confirming in vivo antifungal activity. Irritating and damaging effects from the same plants on skin wounds were not observed, indicating the absence of adverse effects on healthy skin of the tested animals (Masoko et al., 2010a; Masoko, Picard, Eloff, 2010b).

The promising use of medicinal plants in sporotrichosis encourages scientific researchers to find a new antifungal product. However, there are few studies proving the anti-Sporothrix spp. activity of medicinal plants. More studies about safe concentrations of their use must be performed because these plants can present chemical elements with capacity to cause toxic effects (Veiga Jr., Pinto, 2005; Leal et al., 2013). More studies are needed to determine medicinal plants´ safe use with little or no adverse effects in the patient.

CONCLUSION

In vitro studies suggest plants as sources of new promising molecules in the control and treatment of sporotrichosis, especially species belonging to the families Combretaceae, Asteraceae and Lamiaceae. Due to various protocols and methodologies used in the studies, as well as to the different tested concentrations, we emphasize the difficulty in comparing the fungistatic and fungicidal results of plant extracts and it is not possible to attribute the plants with better activity. Furthermore, the lack of in vivo studies of plants was noticed, which reveals the need for deeper studies focussed on the action mechanism of the plants, as well as their toxicity, side effects and possibility of drug interactions in order to understand the safe use of medicinal plants for the treatment of sporotrichosis.

ACKNOWLEDGEMENTS

The authors acknowledge José A. Curbelo Knutson (B.A. International Affairs, The George Washington University Elliott School of International Affairs, Washington, District of Columbia, U.S.A.) for the English translation and revision of the text. Additionally, the authors are grateful to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), to Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS), and to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for student and research scholarships.

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Received: June 22, 2015; Accepted: May 02, 2016

*Correspondence: S. B. Waller.Centro de Diagnóstico e Pesquisa em Micologia Veterinária (MicVet). Departamento de Veterinária Preventiva. Faculdade de Veterinária. Universidade Federal de Pelotas. Campus Universitário Capão do Leão, s/nº - Caixa Postal: 354 - 96010-900 - Pelotas - RS, Brasil. E-mail: waller.stefanie@yahoo.com.br

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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