Implementing polymeric pseudorotaxanes for boosting corneal permeability and antiaspergillus activity of tolnaftate: formulation development, statistical optimization, ex vivo permeation and in vivo assessment.

Fungal keratitis (FK) is a devastating ocular disease that can cause corneal opacity and blindness if not treated effectively. Tolnaftate (TOL) is a selective fungicidal drug against Aspergillus spp. which are among the most common causes of mycotic keratitis. TOL is lipophilic drug with low water solubility and permeation which act as obstacles for its clinical ocular efficacy. Hence, this study aimed to statistically optimize a novel polymeric pseudorotaxanes (PSRs) containing TOL for enhancing its ocular permeability and antifungal effect. For achieving this goal, a full 31.22 factorial design was fashioned for preparing and optimizing TOL-PSRs using film hydration technique. Three formulation variables were studied: drug amount (X1), weight ratio of Pluronics to HPßCD (X2) and Pluronic system (X3). Entrapment efficiency percent (EE%) (Y1), particle size (PS) (Y2) and zeta potential (ZP) (Y3) were set as dependent variables. The selected optimal TOL-PSRs (PSR1) showed EE% of 71.55 ± 2.90%, PS of 237.05 ± 12.80 nm and ZP of -32.65 ± 0.92 mV. In addition, PSR1 was compared to conventional polymeric mixed micelles (PMMs) and both carriers significantly increased the drug flux and resulted in higher amount permeated per unit area in 8 h compared to drug suspension. The histopathological studies assured the safety of PSR1 for ocular use. The in vivo susceptibility testing using Aspergillus niger confirmed that PSR1 displayed sustained antifungal activity up to 24 h. The obtained results revealed the admirable potential of PSR1 to be used as novel nanocarriers for promoting TOL ocular delivery.

Novel therapeutic compounds for prostate adenocarcinoma treatment: An analysis using bioinformatic approaches and the CMap database.

INTRODUCTION: Prostate adenocarcinoma is the most frequently diagnosed malignancy, particularly for people >70 years old. The main challenge in the treatment of advanced neoplasm is bone metastasis and therapeutic resistance for known oncology drugs. Novel treatment methods to prolong the survival time and improve the life quality of these specific patients are required. The present study attempted to screen potential therapeutic compounds for the tumor through bioinformatics approaches, in order to provide conceptual treatment for this malignant disease. METHODS: Differentially expressed genes were obtained from the Gene Expression Omnibus database and submitted into the Connectivity Map database for the detection of potentially associated compounds. Target genes were extracted from the search results. Functional annotation and pathway enrichment were performed for the confirmation. Survival analysis was used to measure potential therapeutic effects. RESULTS: It was revealed that 3 compounds (vanoxerine, tolnaftate, and gabexate) may help to prolong the disease-free survival time from tumor metastasis of patients with the tumor. A total of 6 genes [also-keto reductase family 1 member C3 (AKR1C3), collagen type III α 1 chain (COL3A1), lipoprotein lipase (LPL), glucuronidase, ß pseudogene 11 (GUSBP11), apolipoprotein E (APOE), and collagen type I α 1 chain (COL1A1)] were identified to be the potential therapeutic targets for the aforementioned compounds. CONCLUSION: In the present study, it was speculated that 3 compounds may function as the potential therapeutic drugs of bone metastatic prostate adenocarcinoma; however, further studies verifying vitro and in vivo are necessary.

Tolnaftate inhibits ergosterol production and impacts cell viability of Leishmania sp.

Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. The treatment of all forms of leishmaniasis relies on first-line drug, pentavalent antimonial, and in cases of drug failure, the second-line drug amphotericin B has been used. Besides the high toxicity of drugs, parasites can be resistant to antimonial in some areas of the World, making it necessary to perform further studies for the characterization of new antileishmanial agents. Thus, the aim of the present work was to evaluate the leishmanicidal activity of tolnaftate, a selective reversible and non-competitive inhibitor of the fungal enzyme squalene epoxidase, which is involved in the biosynthesis of ergosterol, essential to maintain membrane physiology in fungi as well as trypanosomatids. Tolnaftate eliminated promastigote forms of L. (L.) amazonensis, L. (V.) braziliensis and L. (L.) infantum (EC50 ~ 10 µg/mL and SI ~ 20 for all leishmanial species), and intracellular amastigote forms of all studied species (EC50 ~ 23 µg/mL in infections caused by dermatotropic species; and 11.7 µg/mL in infection caused by viscerotropic species) with high selectivity toward parasites [SI ~ 8 in infections caused by dermatotropic species and 17.4 for viscerotropic specie]. Promastigote forms of L. (L.) amazonensis treated with the EC50 of tolnaftate displayed morphological and physiological changes in the mitochondria and cell membrane. Additionally, promastigote forms treated with tolnaftate EC50 reduced the level of ergosterol by 5.6 times in comparison to the control parasites. Altogether, these results suggest that tolnaftate has leishmanicidal activity towards Leishmania sp., is selective, affects the cell membrane and mitochondria of parasites and, moreover, inhibits ergosterol production in L. (L.) amazonensis.

Current concepts in systemic and topical therapy for superficial mycoses.

There presently exists a wide selection of choices in the treatment of superficial mycoses. The main categories of broad-spectrum agents are the allylamines and imidazoles, which have been tried and proven over more than 2 decades of usage with good safety. Nystatin and griseofulvin have even longer experience of about 5 decades but have niche usage for yeasts and dermatophytes, respectively. Although no new therapeutic groups have appeared, extensive development of vehicles and delivery systems has enhanced therapeutic results and increased patient compliance.

Micetomas por microsporum canis: caso clínico / Mycetomas by microsporum canis: report of one case

We report and eight years old boy presenting with a pyogenic granuloma of the scalp, generalized alopecia, descamative plates in the neck, trunk and limbs and nail involvement. Cultures for fungus of all these lesions disclosed Microspore canis. The patient was treated with oral griseofulvin, miconazole and topical tolnaftate. Five years later and after several incomplete treatments, the patient returns with a fistulous mass of 12 x 8 cm in the dorsal area whose culture revealed Microspore canis. The mass was excised and oral ketoconazole was indicated. After three months of follow up, the patient was lost from control

Current therapy of dermatophytosis.

In the past dermatophytes were treated with topical agents or, in the case of more recalcitrant or extensive disease, with oral antifungals (griseofulvin or ketoconazole). Topical therapies may be effective in many cases, but they have limitations. They may be viewed as inconvenient by the patient, thereby affecting compliance. Therapy with early oral antifungals entails long treatment periods until complete cure is obtained. For ketoconazole rare but serious side effects can occur, particularly with prolonged use. Griseofulvin is still the drug of choice for the treatment of tinea capitis of the Microsporum type. In recent years a few new antimycotic agents have been developed for systemic therapy of superficial fungal infections. Itraconazole is a broad-spectrum triazole. Fluconazole belongs to the same chemical class and was used mainly in systemic yeast infections and mucosal candidosis. Terbinafine is an allylamine and has been found to be effective and safe in brief therapy of dermatophyte infections. Short-duration therapy of most dermatophyte infections is also possible with itraconazole. The high and specific activity against the causative agents, together with their pharmacokinetic properties, explains the good results obtained with these new drugs and their improved safety profile. Their mode of action, pharmacokinetics, and treatment schedules will be discussed.

[New antifungal agents in the treatment of superficial dermatomycoses]. / Nouveaux antifongiques dans le traitement des mycoses cutanées superficielles.

New antifungals for topical and systemic treatment of superficial mycotic infections of the skin and nails have been developed in the last decade. Terconazole is a potent drug in treating topically vaginal candidiasis. Amorolfine belongs to the chemical class of morpholine derivatives and is topically active against a wide range of fungal infections. Also naftifine and terbinafine, two new allylamines, can be used in local therapy of superficial mycotic infections of the skin. Itraconazole and fluconazole are both new triazoles for systemic use. Itraconazole has a broader spectrum and a higher safety profile than ketoconazole, caused by a greater specificity for the fungal cytochrome P 450 14-alpha-demethylase. The pharmacokinetic properties result in shorter treatments, even in onychomycosis. The mode of action of fluconazole is the same as for the azoles. This drug was being studied particularly in systemic mycoses and mucosal candidiasis. The activity of orally terbinafine is directed mainly against dermatophytes. This drug offers new therapeutic possibilities in the treatment of onychomycosis, caused by dermatophytes.

Tea tree oil in the treatment of tinea pedis.

Tea tree oil (an essential oil derived primarily from the Australian native Melaleuca alternifolia) has been used as a topical antiseptic agent since the early part of this century for a wide variety of skin infections; however, to date, the evidence for its efficacy in fungal infections is still largely anecdotal. One hundred and four patients completed a randomized, double-blind trial to evaluate the efficacy of 10% w/w tea tree oil cream compared with 1% tolnaftate and placebo creams in the treatment of tinea pedis. Significantly more tolnaftate-treated patients (85%) than tea tree oil (30%) and placebo-treated patients (21%) showed conversion to negative culture at the end of therapy (p < 0.001); there was no statistically significant difference between tea tree oil and placebo groups. All three groups demonstrated improvement in clinical condition based on the four clinical parameters of scaling, inflammation, itching and burning. The tea tree oil group (24/37) and the tolnaftate group (19/33) showed significant improvement in clinical condition when compared to the placebo group (14/34; p = 0.022 and p = 0.018 respectively). Tea tree oil cream (10% w/w) appears to reduce the symptomatology of tinea pedis as effectively as tolnaftate 1% but is no more effective than placebo in achieving a mycological cure. This may be the basis for the popular use of tea tree oil in the treatment of tinea pedis.

Antifungal activity of the new agent latoconazole in two tinea models.

In vitro and in vivo antifungal activities of the new imidazole derivative latoconazole ((+-)-(E)-[4-(2-chlorophenyl)-1,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile, NND-318; CAS 101530-10-3) were studied in comparison with three major topical agents, clotrimazole, bifonazole and tolnaftate. The in vitro activity of latoconazole against dermatophytes was much stronger than that of any reference agent tested. Both the recently developed tinea pedis model and the conventional tinea model in guinea pigs were employed for evaluation of topical usefulness of latoconazole. The 1% solution or cream preparation of latoconazole was highly effective in both of the two tinea models and its 5 or more doses achieved almost complete mycological cure. However, both tinea models, especially the former, were considerably resistant to the therapeutic treatment of all of the reference drugs. These results suggest that latoconazole is a promising topical antifungal agent, probably applicable to the treatment of tinea pedis as well as other types of dermatomycoses.

In vitro and in vivo activities of piritetrate (M-732), a new antidermatophytic thiocarbamate.

Piritetrate (M-732), a new topical antifungal agent belonging chemically to the thiocarbamates, was demonstrated to possess a potent selective antidermatophytic activity. In terms of its MICs in susceptibility testing, mainly done by using Sabouraud dextrose agar plates, piritetrate exhibited several- to 10-fold-stronger antidermatophytic activity than tolnaftate, a reference thiocarbamate. Furthermore, piritetrate was found to show a broader antifungal spectrum than tolnaftate; relatively many species and strains of dematiaceous fungi, dimorphic fungi, and some other filamentous fungi as well as a few strains of Cryptococcus neoformans were fairly susceptible to piritetrate, while almost all the tested species and strains were resistant to tolnaftate. All the tested species of the genus Candida were, however, resistant to both compounds. Variables which can influence antimicrobial activity caused few changes in the MICs of either compound against Trichophyton mentagrophytes; however, an increase in the inoculum size resulted in a significant increase in the MICs. The antidermatophytic activities of piritetrate and tolnaftate were fungistatic but not fungicidal. Piritetrate also exhibited a more potent in vitro anti-T. mentagrophytes activity than clotrimazole or tolciclate. Piritetrate and tolnaftate had no antibacterial activity. The in vivo activity of topically administered piritetrate against experimental dermal infection of guinea pigs with T. mentagrophytes was more effective than that of tolnaftate both mycologically and clinically. Piritetrate manifested no acute toxicity in laboratory animals when administered even in large quantities by the oral, intraperitoneal, and topical routes.

Uso do creme de oxiconazol a 1% no tratamento de dermatofitoses / Use of 1% oxiconazole cream in the treatment of dermatophytosis

Vinte e oito pacientes com diagnóstico clínico e laboratorial de dermatofitose foram aleatoriamente divididos em dois grupos. Um grupo foi tratado com creme de oxiconazol a 1%. O outro grupo foi tratado com creme de tolnaftato. A medicaçäo em ambos os grupos foi aplicada duas vezes ao dia por 40 dias. Em uma segunda fase foram estudados 19 pacientes com diagnóstico clínico e laboratorial de dermatofitose, tratados com uma única aplicaçäo diária de creme de oxiconazol a 1% por 40 dias. O creme de oxiconazol a 1% foi täo eficaz quanto o creme de tolnaftato e causou menor incidência de efeitos colaterais. uma única aplicaçäo diária de creme de oxiconazol a 1% levou à cura micológica em 94,7% dos pacientes após 40 dias

Current treatment of dermatophytoses.

There is a wide variety of highly effective topical antifungal agents available for the treatment of dermatophytosis. In more widespread infections or those involving hair or nails oral therapy with griseofulvin or ketoconazole can be used. With both forms of therapy certain types of dermatophyte infection are clinically resistant to treatment. These include onychomycosis, infections of the sole caused by T.rubrum and certain forms of tinea capitis (e.g. favus) or tinea corporis. In future consideration needs to be given to find the optimum duration and frequency of treatment and better methods of allowing penetration of drugs into nails and heavely keratinised sites.

Antifungal therapy of dermatophytosis in guinea pigs and congenitally athymic rats.

Guinea pigs and athymic nude (RNU/RNU) rats were used to assess the efficacy of three orally administered antifungal agents--Tolciclate, Tolnaftate, and Ketoconazole--against Trichophyton mentagrophytes dermatophytosis. All three antifungal agents inhibited the test strain of T. mentagrophytes in vitro. Antifungal agents were tested in intervention (oral therapy started 5 days after challenge) or prophylaxis (oral therapy started 5 days before challenge) protocols. Oral treatment of dermatophytosis on guinea pig skin demonstrated that Tolciclate and Tolnaftate alleviated clinical symptoms and shortened the duration of the dermatophytosis, in comparison to nontreated controls. Assessment of antifungal efficacy in the guinea pig model was time consuming (30-35 days) and variability in the duration and severity of clinical symptoms on guinea pig skin was common. Oral therapy of chronically infected athymic rats demonstrated that Tolciclate, Tolnaftate, and ketoconazole were effective antifungal agents in vivo. Obvious improvement in clinical symptoms of dermatophytosis (i.e. less erythema and fewer lesions) was evident with all three antifungal agents within 10 days of starting oral therapy. By day 20, athymic rats that were treated with either Tolciclate or Ketoconazole showed marked clinical improvement of the chronic dermatophytosis. Chronically infected athymic rats, which lack thymus matured T-cells, are a promising new model to evaluate the efficacy of antifungal agents by culture, histology, and visual observations of clinical symptoms.

[Dermatophytosis caused by Aphanoascus fulvescens]. / Dermatofitosis por Aphanoascus fulvescens.

Aphanoascus fulvescens was isolated from lesions resembling a dermatophyte infection in a 45-year-old woman who had used steroid cream for several months to treat a dermatosis of the neck. Treatment with griseofulvin and tolnaftate cured the lesions in 6 weeks. The microscopic characteristics of the isolate and its size differed slightly from those described by several other authors, and bore a closer resemblance to isolates previously described from Australia and New Guinea.