anti-Candida Agents Research Articles

Vitis Vinifera L.: A new bioactive anticandidal agent to combat oral candidal carriage in Down syndrome patients.

Down syndrome (DS) patients have a high risk of opportunistic infections from Candida species. Therefore, the purpose of this research was to assess the prevalence of Candida species in oral cavity of DS patients and investigating of grape seed extract (GSE) as a potential anticandidal agent. Our study included fifty patients with DS and fifty healthy children. Oral tongue swabs were taken from both groups and isolated Candida species were identified. The anticandidal activity of GSE against isolated Candida was studied using agar well diffusion method. Scanning electron microscope (SEM) was used to determine the major alterations in Candida after GSE treatment. GSE was subjected to GC-MS analysis and HPLC analysis. Forty six samples showed growth of Candida in DS group, where as ten samples in control group. The most common pathogenic Candida isolated from DS patients was C.tropicalis (65.2%). GSE showed significant inhibitory activity against C.tropicalis (MIC 30 mg/ml). The SEM showed complete alterations in Candida cell morphology. GC-MS chromatogram of GSE revealed 30 compounds, the major one is (9, 12-Octadecadienoic acid) which confirmed by HPLC chromatogram with a peak at RT 20.311 min. GSE could be a promising anticandidal agent and it may form a primary platform for further toxicological assessment and development of new drugs.

In Vitro and In Vivo Anti-Candida spp. Activity of Plant-Derived Products.

Candidiasis therapy, especially for candidiasis caused by Candida non-albicans species, is limited by the relatively reduced number of antifungal drugs and the emergence of antifungal tolerance. This study evaluates the anticandidal activity of 41 plant-derived products against Candida species, in both planktonic and biofilm cells. This study also evaluates the toxicity and the therapeutic action of the most active compounds by using the Caenorhabditis elegans–Candida model. The planktonic cells were cultured with various concentrations of the tested agents. The Cupressus sempervirens, Citrus limon, and Litsea cubeba essential oils as well as gallic acid were the most active anticandidal compounds. Candida cell re-growth after treatment with these agents for 48 h demonstrated that the L. cubeba essential oil and gallic acid displayed fungistatic activity, whereas the C. limon and C. sempervirens essential oils exhibited fungicidal activity. The C. sempervirens essential oil was not toxic and increased the survival of C. elegans worms infected with C. glabrata or C. orthopsilosis. All the plant-derived products assayed at 250 µg/mL affected C. krusei biofilms. The tested plant-derived products proved to be potential therapeutic agents against Candida, especially Candida non-albicans species, and should be considered when developing new anticandidal agents.

Anticandidal agent for multiple targets: the next paradigm in the discovery of proficient therapeutics/overcoming drug resistance.

Candida albicans is a prominent human fungal pathogen. Current treatments are suffering a massive gap due to emerging resistance against available antifungals. Therefore, there is an ardent need for novel antifungal candidates that essentially have more than one target, as most antifungal repertoires are single-target drugs. Exploration of multiple-drug targeting in antifungal therapeutics is still pending. An extensive literature survey was performed to categorize and comprehend relevant studies and the current therapeutic scenario that led researchers to preferentially consider multitarget drug-based Candida infection therapy. With this article, we identified and compiled a few potent antifungal compounds that are directed toward multiple virulent targets in C. albicans. Such compound(s) provide an optimistic platform of multiple targeting and could leave a substantial impact on the development of effective antifungals.

Design and Synthesis of Novel 1,3-Thiazole and 2-Hydrazinyl-1,3-Thiazole Derivatives as Anti-Candida Agents: In Vitro Antifungal Screening, Molecular Docking Study, and Spectroscopic Investigation of their Binding Interaction with Bovine Serum Albumin.

In the context of there being a limited number of clinically approved drugs for the treatment of Candida sp.-based infections, along with the rapid development of resistance to the existing antifungals, two novel series of 4-phenyl-1,3-thiazole and 2-hydrazinyl-4-phenyl-1,3-thiazole derivatives were synthesized and tested in vitro for their anti-Candida potential. Two compounds (7a and 7e) showed promising inhibitory activity against the pathogenic C. albicans strain, exhibiting substantially lower MIC values (7.81 μg/mL and 3.9 μg/mL, respectively) as compared with the reference drug fluconazole (15.62 μg/mL). Their anti-Candida activity is also supported by molecular docking studies, using the fungal lanosterol C14α-demethylase as the target enzyme. The interaction of the most biologically active synthesized compound 7e with bovine serum albumin was investigated through fluorescence spectroscopy, and the obtained data suggested that this molecule might efficiently bind carrier proteins in vivo in order to reach the target site.

Synthesis and Characterization of Novel Five-Membered Heterocycles and Their Activity against Candida Yeasts

Some new tetrazole derivatives were prepared by the reaction between the prepared azomethine compounds I6-I10 with sodium azide in anhydrous tetrahydrofuran (THF) with a few drops of distilled water and under reflux conditions. Azomethine compounds were prepared by thermal condensation reactions of aromatic aldehydes with primary aromatic amines. The prepared compounds (tetrazole derivatives) were screened for their antibacterial activity (by disc diffusion method). Compound I6 is the most active derivative that has recorded a significantly (p<0.01) stronger influence to inhibit the growth of Candida zeylanoides with an average zone of inhibition of 26.0 mm. Derivatives I7 and I9 showed the lowest zone of inhibition of 8.0 mm against Candida zeylanoides. This study may be helpful in designing more potential anticandidal agents for therapeutic use in the future.

Proteomic analysis uncovers the modulation of ergosterol, sphingolipid and oxidative stress pathway by myristic acid impeding biofilm and virulence in Candida albicans

Candida albicans, a dimorphic opportunistic fungus is known to form robust biofilm and commonly associated with superficial and life threatening systemic infections. The repertoire of C. albicans infection is comprehensive due to its biofilm mediated virulence and occurrence of resistance against conventional antifungal drugs. Natural bioactive compounds are known for their antivirulence potency against fungi circumventing their resistance. In the present study, antibiofilm and antihyphal efficacies of myristic acid (MA), a major component of Myristica fragrans against C. albicans was assessed. Results of biofilm assays, optical microscopic analyses showed the potent inhibition of biofilm and hyphal formation by MA at 125 μg mL−1. Proteomic analysis revealed the ability of MA to target proteins involved in various virulence pathways such as ergosterol synthesis, sphingolipid metabolism, multidrug resistance and the oxidative stress. The results of gene expression analysis and biochemical assays validated the outcomes of proteomic analysis. This investigation emphasized the potent antibiofilm and virulence inhibitory potentials of MA. Hence, MA could be clinically utilized to control infections caused by C. albicans. Biological significanceThe conventional antifungal drugs acquire single target pattern by regulating either sterol synthesis or drug efflux pump in C. albicans that ushers drug-resistance. But Myristic acid attenuates C. albicans virulence by negative regulation of proteins involved in sterol synthesis & uptake, sphingolipids and antioxidant activity. In the current study, the multi-target efficacy and the ability to inhibit biofilm and hyphae mediated virulence factors without affecting the cellular metabolism of C. albicans marks myristic acid as a potent anti-candida agent against drug resistant Candida species.

QSAR Study of Some 1,3-Oxazolylphosphonium Derivatives as New Potent Anti-Candida Agents and Their Toxicity Evaluation.

The incidence of invasive fungal infections caused by Candida spp. has increased continuously in recent decades, especially in populations of immunocompromised patients or individuals hospitalized with serious underlying diseases. Therefore, the goal of our study was the search for new potent Candida albicans inhibitors via the development of QSAR models that could speed up this search process. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and experimentally tested. Furthermore, the toxicity of the studied compounds was determined in vitro using acetylcholinesterase enzyme as a biological marker. The classification QSAR models were created using Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks methods and different combinations of descriptors on the Online Chemical Modeling Environment (OCHEM) platform. Аntifungal properties of the investigated compounds were performed using standard disk diffusion method. The enzyme inhibitory action of the compounds was determined by modified Ellman's method using acetylcholinesterase from the electric organ of Electrophorus electricus. Three classification QSAR models were developed by the WEKA-RF, k-NN and ASNN methods using the ALogPS, E-State indices and Dragon v.7 descriptors. The predictive ability of the models was tested through cross-validation, giving a balanced accuracy BA = 80-91%. All compounds demonstrated good antifungal properties against Candida spp. and slight inhibition of the acetylcholinesterase activity. The high percentage of coincidence between the QSAR predictions and the experimental results confirmed the high predictive power of the developed QSAR models that can be applied as tools for finding new potential inhibitors against Candida spp. Furthermore, 1,3-oxazol-4- yl(triphenyl)phosphonium salts could be considered as promising candidates for the treatment of candidiasis and the disinfection of medical equipment.

The beneficial effect of Indonesian propolis wax from Tetragonula sp. as a therapy in limited vaginal candidiasis patients.

Vaginal candidiasis characterized by abnormal vaginal discharge and itching usually treated by azole’s drug or nystatin; however, some results of treatment are unsatisfied and become recurrent. Propolis containing polyphenols and flavonoids is known to have anti-inflammatory and antimicrobial activity. This study investigated the effect of Indonesian propolis wax from Tetragonula sp. as a therapy in limited vaginal candidiasis patients. The subjects were women who came to the Tasik Community Health Centre met the inclusion criteria such as clinical complaint and laboratory evaluation (positive hyphae/pseudohyphae and culture on Sabouraud Dextrose Agar (SDA) medium) from a vaginal swab. Evaluation of anti-candida effect of propolis was determined by clinical remission and the absence of Candida’s growth on SDA medium. Forty subjects were randomly assigned to those receiving treatment by ovule propolis (n = 20) and that treatment by nystatin (n = 20) as a control, once daily, for seven days, respectively. All methods have been approved by the Ethics Commission of the Faculty of Medicine, Universitas Indonesia. Our results indicated no significant difference in the laboratory evaluation of patients who have treated ovule propolis compared to standard therapy. This study suggests that propolis wax has a beneficial effect to develop as an anti-candida agent for vaginal candidiasis therapy.

Anticandidal Potential of Stem Bark Extract from Schima superba and the Identification of Its Major Anticandidal Compound.

Plant-derived extracts are a promising source of new drugs. Schima superba is traditionally used in China for heat clearing, detoxification, and treatment of furuncles. In this study, the anticandidal properties and mechanism of action of S. superba (SSE) were explored using a stem bark extract. SSE possessed high polyphenol and saponin contents of 256.6 ± 5.1 and 357.8 ± 31.5 µg/mg, respectively. A clear inhibition zone was observed for C. albicans growth through the disc diffusion method and the 50% inhibition of C. albicans by SSE was 415.2 µg/mL. Transcriptomic analysis in C. albicans treated with different doses of SSE was conducted through RNA-seq. Average values of 6068 genes and 20,842,500 clean reads were identified from each sample. Among these samples, 1680 and 1956 genes were differentially expressed genes (DEGs) from the SSE treatments of 0.2 and 0.4 mg/mL, respectively. C. albicans growth was inhibited by the changes in gene expression associated with the cell wall and membrane composition including the regulation of chitin degradation and ergosterol biosynthesis. This result could be reflected in the irregularly wrinkled morphology of the ruptured cell as revealed through SEM analysis. ESI-MS and NMR analyses revealed that the major compound purified from SSE was sasanquasaponin III and the 50% inhibition of C. albicans was 93.1 µg/mL. In summary, the traditional Chinese medicine S. superba can be applied as an anticandidal agent in complementary and alternative medicine.

Recent Advances in Azole Based Scaffolds as Anticandidal Agents

Aim:The present review aims to explore the development of novel antifungal agents, such as pharmacology, pharmacokinetics, spectrum of activity, safety, toxicity and other aspects that involve drug-drug interactions of the azole antifungal agents.Introduction:Fungal infections in critically ill and immune-compromised patients are increasing at alarming rates, caused mainly by Candida albicans an opportunistic fungus. Despite antifungal annihilators like amphotericin B, azoles and caspofungin, these infections are enormously increasing. The unconventional increase in such patients is a challenging task for the management of antifungal infections especially Candidiasis. Moreover, problem of toxicity associated with antifungal drugs on hosts and rise of drug-resistance in primary and opportunistic fungal pathogens has obstructed the success of antifungal therapy.Conclusion:Hence, to conflict these problems new antifungal agents with advanced efficacy, new formulations of drug delivery and novel compounds which can interact with fungal virulence are developed and used to treat antifungal infections.

Biocompatible Tin Oxide Nanoparticles: Synthesis, Antibacterial, Anticandidal and Cytotoxic Activities

AbstractBiocompatible SnO2 NPs, were synthesized by simple and facile ultrasonic technique, and further studied for antibacterial, anticandidal and invitro cytotoxic activity. The obtained size of synthesized SnO2 NPs, was 5–30 nm and characterized by X‐ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). The evaluation of antibacterial and anticandidal activity of the SnO2 NPs, was done by determining the minimum inhibitory concentration (MIC), and minimum bactericidal/fungicidal concentration (MBC/MFC), against Escherichia coli and Candida albicans, respectively. The MIC of 0.5 mg/ml and MBC of &gt;1 mg/ml for E. coli, while as the MIC of 8 mg/ml and MFC &gt;16 mg/ml for C. albicans, was obtained. Maximum activity for both, bacteria and Candida was achieved, however, to the best of our knowledge, this is the first report of anticandidal activity exhibited by SnO2 NPs. Treatment of synthesized SnO2 NPs against the colorectal (HCT‐116) cancer cell line, decreased the cell survivability in a dose‐dependent manner, as lower dose showed decrease of 73.00%, whereas, higher dosage caused a significant 31.34% decrease in the cell viability. The obtained results confirmed, that the prepared SnO2 NPs can be the future broad‐spectrum antibacterial, anticandidal and anticancer agent, and can be further explored for application in the biomedical field.

In silico study of 4-phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6-bisphosphate aldolase II

In this study, the synthesis, in vitro anti-Candida activity and molecular modeling of 4-phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6-bisphosphate aldolase (FBA-II) are demonstrated and discussed. Significant similarity of the primary and secondary structure, binding sites and active sites of FBA-II C. albicans and Mycobacterium tuberculosis are established. FBA-II C. albicans inhibitors contained 1,3-oxazole-4-phosphonates moiety are created by analogy to inhibitors FBA-II M. tuberculosis. The experimental studies of the anti-Candida activity of the designed and synthesized compounds have shown their high activity against standard strain and its C. albicans fluconazole resistant clinical isolate. It was hypothesized that the growth suppression of fluconazole-resistant С. albicans strain may be due to the inhibition of aldolase fructose-1,6-bisphosphate. A qualitative homology 3D model of the C. albicans FBA-II was created using SWISS-MODEL server. The probable mechanism of FBA-II inhibition by studied 4-phosphorylated derivatives was shown using molecular docking. The main role of amino acid residues His110, His226, Gly227, Leu248, Val238, Asp144, Lys230, Glu147, Gly227, Ala112, Leu145 and catalytic zinc atom in the formation of stable ligand-protein complexes with ΔG = –6.89, –7.2, –7.16, –7.5, –8.0, –7.9 kcal/mol was shown.Thus, the positive results obtained in the work were demonstrated the promise of using the proposed homology 3D model of the C. albicans FBA-II as the target for the search and development of new anti-Candida agents against azole-resistant fungal pathogens. Designed and studied 4-phosphorylated derivatives of 1,3-oxazole having a direct inhibiting FBA-II molecular mechanism of action can be used as perspective drug-candidates against resistant C. albicans strains.

QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP STUDY ON THE INHIBITORY ACTIVITY OF COPPER SCHIFF BASE COMPLEXES AGAINST CANDIDA ALBICAN

Quantitative Structure Activity Relationship (QSAR) study was performed on Copper Schiff base complexes. Multiple Linear Regression analysis and genetic function algorithms was employed to derive QSAR model for better activity. The derived QSAR model having Squared Correlation Coefficient R 2 = 0.8345, Cross Validation Squared Correlation Coefficient Q 2 = 0.6681 and predicted R squared (R 2 pred ) = 0.5980. The predictive ability of the derived model was also confirmed by internal and external cross validation techniques. The QSAR model indicate that the descriptors (MATS4p) Moron autocorrelation of lag 4 weighed by polarizability,(RCI) Ring Complexity index, (G2m) 2 nd component symmetry directional WHIM index/weighted by mass, BI0 [N-O] Presence/absence of N-O at topological distance 10 and (nF) Number of Fluorine atoms plays an important role in predicting the activities against anti-candida albican. The result obtained in this study was used in designing more potent Copper Complexes as anti-candida albican agents.

Synthesis and Antifungal Potential of Some Novel Benzimidazole-1,3,4-Oxadiazole Compounds.

Discovery of novel anticandidal agents with clarified mechanisms of action, could be a rationalist approach against diverse pathogenic fungal strains due to the rise of resistance to existing drugs. In support to this hypothesis, in this paper, a series of benzimidazole-oxadiazole compounds were synthesized and subjected to antifungal activity evaluation. In vitro activity assays indicated that some of the compounds exhibited moderate to potent antifungal activities against tested Candida species when compared positive control amphotericin B and ketoconazole. The most active compounds 4h and 4p were evaluated in terms of inhibitory activity upon ergosterol biosynthesis by an LC-MS-MS method and it was determined that they inhibited ergosterol synthesis concentration dependently. Docking studies examining interactions between most active compounds and lanosterol 14-α-demethylase also supported the in vitro results.

A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies.

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the binding poses towards lanosterol 14α-demethylase. An in silico ADMET analysis showed that the compounds possess drug-like properties and represent a biologically active framework that should be further optimized as potential hits.

Original Research Article (Experimental): Targeting fungal menace through copper nanoparticles and Tamrajal

BackgroundWHO reports, an escalation of antibiotic resistance in opportunistic pathogens like Candida. Tamrajal, i.e., water stored in copper vessels has been proclaimed as health elixir by ancient Ayurveda. Vis-a-Vis the use of copper contact surfaces and nanoparticles has gained significance for their antimicrobial effects. It thus seems imperative to examine copper nanoparticles and tamrajal as promising alternatives to existing antifungals. ObjectiveThis study not only assessed the influence of Tamrajal and copper nanoparticles on the morphological alterations of the Candida and its biofilm forming ability, but also on their ability to destroy preformed biofilms. Materials and methodsCopper oxide nanoparticles as well as Tamrajal were evaluated as complementary as well as stand-alone antimicrobial agents. ‘Time kill assay’ and ‘germ tube inhibition test’ were performed as end-point analysis for pathogenesis, while biofilm quantification, performed to assess the colonizing capability of Candida. Scanning Electron Microscope was used for visualizing the cells, whilst ICP-AES to determine the copper concentration. Results92–100% cytotoxicity to the fluconazole resistant Candida species was observed with copper oxide nanoparticles as well as tamrajal during 24hr time kill assay. The study also confirmed complete germ tube inhibition by copper in both its forms in addition to the reduction in the biofilm production. ConclusionCompared to the classes of antifungals like azoles, echinocandins etc, copper based anti-candidal agents highlight a potential way to combat resistant candidiasis. The possibility of accumulation of NP resulting in cytotoxicity puts tamrajal as the choice due to its efficacy as well as non-toxicity as per the EPA.

Antifungal effect of the bark and root extracts of Punica granatum on oral Candida isolates.

Background and Purpose:Oral candidiasis is one of the most common fungal infections in humans. The treatment and prophylaxis of the patients suffering from this infection require the identification of new anti-Candida agents with no side effects or toxicity like medicinal plants. The present study was conducted to compare the antifungal activities of the aqueous, ethanolic, and methanolic extracts of the bark and roots of P. granatum with those of two routine antifungal agents (i.e., fluconazole and nystatin) on oral Candida strains isolated from liver transplant recipients.Materials and Methods:Minimum inhibitory concentrations (MICs) of the ethanolic, methanolic, and aqueous extracts of the bark and root of Punica granatum against C. albicans and C. glabrata isolated from oral cavities were evaluated according to the CLSI M27-A3. All data were analyzed in SPSS (version 16.0) by pairwise comparison and Kruskal-Wallis test.Results:The MIC50 and MIC90 values for the methanolic and ethanolic extracts of the bark and root of P. granatum against C. albicans were both obtained as 0.05 mg/ml with the geometric mean (GM) of 0.07. Furthermore, the MIC90 values for the aqueous extracts of bark and root were estimated as 0.05 and 0.2 mg/ml, respectively. With regard to C. glabrata, the MIC50 and MIC90 values for the methanolic and ethanolic extracts of the bark and root were 0.05 mg/ml. However, the MIC90 value for the aqueous extract against this species was obtained as 25 mg/ml. The GM values for the aqueous extracts of the bark and root were 9.49 and 0.32, respectively.Conclusion:As the findings indicated, the methanolic and ethanolic extracts of the bark and root of Punica granatum had anti-Candida activities. Therefore, they can be considered as mouthwash or toothpaste to prevent and treat Candida infections in the oral cavity.

Clotrimazole multiple W/O/W emulsion as anticandidal agent: Characterization and evaluation on skin and mucosae.

Clotrimazole (CLT) was formulated in a multiple W/O/W emulsion (ME) with the aim of evaluating its potential as topical anticandidal agent and comparing with marketed products. A previously evaluated CLT-ME was selected and physicochemically characterized. The in vitro release behavior and the ex vivo permeation profiles were assessed using Franz diffusion cells using three different types of biological membranes: human skin and porcine buccal, sublingual and vaginal mucosae. The antifungal activity against Candida strains was also tested. Results showed CLT-MEs sizes of 29.206 and 47.678 μm with skin compatible pH values of 6.47 and 6.42 exhibiting high zeta potential values of -55.13 and -55.59 mV with dependence on the pH variation. The physicochemical stability was kept for a period of 180 days of storage at room temperature. CLT-MEs exhibited pseudoplastic behavior with hysteresis areas and viscosities of 286 and 331 mPa⋅s showing higher spreadability properties than commercial counterparts. An improved CLT release pattern was supplied by the ME system following a hyperbolic model. Likewise, ME system gave higher skin permeation flux of CLT than commercial reference. CLT amounts retained in the skin and mucosae were also higher than commercial references, which coupled with the higher antimycotic efficacy make CLT-MEs a great tool for clinical investigation of topical candidiasis treatments.

Natural Products for Vulvovaginal Candidiasis Treatment: Evidence from Clinical Trials.

Candida albicans is an opportunistic yeast that causes more than 90% of all vulvovaginal infections. Because of being inherently resistant to antifungals drugs such as azole derivatives, the search for anti-Candida albicans agents with new pharmacological targets is considered as the main therapeutic strategy to prevent and treat these types of infections. In this context, products of natural origin are a promising source of compounds with antifungal activity. The current review analyzes clinical evidence on the effectiveness of natural products in the vulvovaginal Candida albicans infections. A literature review in the electronic databases PubMed, Google Scholar, Cochrane Library Plus, Web of Science, Latin American and Caribbean Literature on Health Sciences (Lilacs) and Scientific Electronic Library Online (SciELO) using the search terms "Natural Products", "Phytotherapy", "Vulvovaginal Candidiasis" and "Clinical Trials" together with the Boolean term 'AND' was performed. English, Spanish and French articles without restriction of date of publication were considered. A total of 13 clinical trials (most of them randomized clinical trials which used azoles as control group) evaluated the anti-Candida activity of a total of 11 different natural products (i.e. Zataria multiflora essential oils, Ageratina pichinchensis and Solanum nigrescens extracts and saponins from Solanum chrysotrichum, among others) against vulvovaginitis have been included in the current review. Because of the few clinical trials it is difficult to establish a consistent conclusion about the effectiveness of natural products in the prevention and treatment of vulvovaginitis caused by Candida albicans. Future studies should be aimed at evaluating new natural products as well as conducting more clinical research with promising natural substances already investigated in clinical trials.

Biopharmaceutical profile of a clotrimazole nanoemulsion: Evaluation on skin and mucosae as anticandidal agent

Clotrimazole (CLT) was formulated in a nanoemulsion (NE) for the topical treatment of candidiasis consisting of 10% labrafac® lipophile, 60% labrasol®:capryol® 90 mixture (ratio 4:1) and 30% propylene glycol. Physicochemical properties, stability, rheology, in vitro drug release, ex vivo drug permeation through human skin and porcine buccal, sublingual and vaginal mucosae, antifungal efficacy, as well as in vivo skin tolerance were evaluated. 1% CLT-NE (CLT-NE1) and 2% CLT-NE (CLT-NE2) exhibited 153 ± 17.25 and 186 ± 15.38 nm droplet sizes, low polydispersity indexes, negative zeta potentials and biocompatible pH values. The CLT-NEs exhibited typical Newtonian profiles with viscosities of 42.14 ± 0.037 mPa·s and 41.35 ± 0.041 mPa·s, respectively and higher extensibility properties than commercial counterparts retaining their physicochemical properties for 180 days. NEs provided a sustained release of drug according to the first order model. Similar skin permeation properties were observed between CLT-NE1 and commercial reference. However, significant higher CLT amounts retained in mucosae were provided by CLT-NE2 when compared with references. Antifungal efficacies were also higher than commercial references, and the in vivo tolerance study confirmed the suitability for topical application, making CLT-NEs a great tool for clinical investigation of topical candidiasis treatments.