Prior selection of itraconazole in the treatment of recalcitrant Trichophyton indotineae infection: Real-world results from retrospective analysis.

BACKGROUND: The number of terbinafine-resistant Trichophyton indotineae is increasing in recent years while the treatment is still a matter to discuss. OBJECTIVES: To explore the best therapeutic approach, we present real-world treatment of T. indotineae infection by analysing publicly available data. METHODS: We have reviewed all published articles, mainly including case reports and case series, on the drug-resistant T. mentagrophytes complex by using the key search terms to search the databases. RESULTS: We enrolled 25 articles from 14 countries, including 203 times of treatment information for 113 patients. The cure rate of itraconazole 200 mg per day at the fourth, eighth and the twelfth week were 27.27%, 48.48% and 54.55%, respectively, which was significantly higher than terbinafine 250 mg per day (8.77%, 24.56% and 28.07%) and even 500 mg/d terbinafine. Griseofulvin 500-1000 mg for 2-6 months may be effective while fluconazole had no record of successful treatment. Voriconazole and ravuconazole had potential therapeutic efficacy. Topical therapy alone showed limited therapeutic efficacy, but the combination with oral antifungals can be alternative. CONCLUSION: Oral itraconazole 200 mg per day for 4-8 weeks was the most effective treatment out of these commonly used antifungal drugs, and can be prior selection.

Antidermatophytic activity of synthetic peptides: Action mechanisms and clinical application as adjuvants to enhance the activity and decrease the toxicity of Griseofulvin.

BACKGROUND: Dermatophytes belonging to the Trichophyton genus are important human pathogens, but they have developed resistance to griseofulvin, the most common antifungal drug used to treat dermatophytosis. OBJECTIVE: This study was aimed to evaluate the antidermatophytic activity of synthetic peptides, as well as mechanisms of action and synergistic effect with griseofulvin. METHODS: Scanning electron microscopy (SEM), atomic force microscopy (AFM) and fluorescence microscopy (FM) were employed to understand the activity and the mechanism of action of peptides. RESULTS: Here we report that synthetic peptides at 50 µg/mL, a concentration 20-fold lower than griseofulvin, reduced the microconidia viability of T. mentagrophytes and T. rubrum by 100%, whereas griseofulvin decreased their viability by only 50% and 0%, respectively. The action mechanism of peptides involved cell wall damage, membrane pore formation and loss of cytoplasmic content. Peptides also induced overproduction of reactive oxygen species (ROS) and enhanced the activity of griseofulvin 10-fold against both fungi, suggesting synergistic effects, and eliminated the toxicity of this drug to human erythrocytes. Docking analysis revealed ionic and hydrophobic interactions between peptides and griseofulvin, which may explain the decline of griseofulvin toxicity when mixed with peptides. CONCLUSION: Therefore, our results strongly suggest six peptides with high potential to be employed alone as new drugs or as adjuvants to enhance the activity and decrease the toxicity of griseofulvin.

Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.

A new griseofulvin derivative from a soft coral-derived fungus Eupenicillium sp. SCSIO41208.

A new griseofulvin derivative, eupenigriseofulvin (1), together with six known compounds, griseofulvin (2), dechlorogriseofluvin (3), dechloroisogriseofulvin (4), trichopyrone (5), 2-(4-hydroxyphenyl)-ethanol (6), and 1-phenylethane-1,2-diol (7), were isolated from the EtOAc extract of Eupenicillium sp. SCSIO41208. The structures of these compounds were elucidated by spectroscopic methods including NMR and mass spectrometry. The absolute configuration of 1 was determined on the basis of electronic circular dichroism (ECD) data analysis.

Melokhanines A-J, Bioactive Monoterpenoid Indole Alkaloids with Diverse Skeletons from Melodinus khasianus.

The new melokhanines A-J (1-10) and 22 known (11-32) alkaloids were isolated from the twigs and leaves of Melodinus khasianus. The new compounds and their absolute configurations were elucidated by extensive analysis of spectroscopic, X-ray diffraction, and computational data. Melokhanine A (1), composed of a hydroxyindolinone linked to an octahydrofuro[2,3-b]pyridine moiety, is an unprecedented monoterpenoid indole alkaloid. Melokhanines B-H (2-8) possess a new 6/5/5/6/6 pentacyclic indole alkaloid skeleton. Alkaloids 1-16, 25-27, 31, and 32 showed the best antibacterial activity against Pseudomonas aeruginosa (MIC range 2-22 µM). Among the seven dermatophytes tested, compound 1 showed significant inhibitory activity against Microsporum canis, M. ferrugineum, and Trichophyton ajelloi (MIC range 38-150 µM), i.e., half the efficacy of the positive control, griseofulvin.

Induction of microtubule damage in Allium cepa meristematic cells by pharmaceutical formulations of thiabendazole and griseofulvin.

Microtubules (MT) are formed by the assembly of α- and ß-tubulins and MT-associated proteins. We characterized the effects of pharmaceutical formulations containing the microtubule disruptors thiabendazole (TBZ) and griseofulvin (GF) on the mitotic machinery of plant (A. cepa) meristematic cells. GF concentrations between 10 and 250 µg/ml were tested. GF induced mitotic index inhibition and genotoxic effects, including chromosome fragments, bridges, lagged chromosomes, C-metaphases, tripolar cell division, disorganized anaphases and nuclear abnormalities in interphase cells. Efects on the mitotic machinery were studied by direct immunofluorescence with ß-tubulin labeling and by DNA counterstaining with 4',6-diamidino-2-phenylindole (DAPI). Exposure of meristematic root cells to TBZ or GF, 100 µg/ml, caused microtubular damage which led to abnormal MT arrays. Our results suggest that GF induces abnormalities in spindle symmetry/polarity, while TBZ causes chromosome missegregation, polyploidy, and lack of cytokinesis.

Evaluation of wound healing and antimicrobial potentials of Ixora coccinea root extract.

OBJECTIVE: To evaluate the wound healing and antimicrobial activity of root extracts of Ixora coccinea (I. coccinea). METHODS: To investigate the wound healing efficacy of root extract of I. coccinea Linn, five groups of animals were divided each containing six animals. Two wound models including incision and excision wound models were used in this study. The parameters studied were tensile strength on incision wound model and in terms of wound contraction for excision wound model were compared with standard Nitrofurazone (NFZ) ointment (0.2% w/w). Six extracts (ethanol, aqueous, petroleum ether, benzene, chloroform and ethyl acetate) of I. coccinea were screened for in vitro growth inhibiting activity against different bacterial strains viz, Staphylococcus aureus, Bacillus pumilius, Enterococcus faecalis, Escherichia coli, Salmonella typhi and Pseudomonas aeruginosa and fungi Candida albicans and Aspergillus niger were compared with the standard drugs ciprofloxacin and chloramphenicol for antibacterial and griseofulvin for antifungal screening. The serial dilution and cup (or) well plate methods were used for the antimicrobial study and MIC was determined. RESULTS: The ethanolic extract showed significant (P<0.001) wound healing activity when compared to standard drug NFZ with respect to normal control group. Amongst all, ethanolic extract showed highly significant antibacterial activity against all bacterial strains used in this study when compared to standard. The aqueous extract showed moderate significant inhibition against all bacterial strains when compared to standard. All the extracts were shown negligible activity against the fungal strains used in this study. CONCLUSIONS: The ethanolic root extract of I. coccinea showed pronounced wound healing and antibacterial activity. The probable reason to heal the wound was that the external application of the extract prevented the microbes to invade through the wound thus the protection of wound occurs against the infection of the various organisms.

A random comparative study of terbinafine versus griseofulvin in patients with tinea capitis in Western China.

OBJECTIVE: To compare the efficacy and safety of terbinafine with griseofulvin in the treatment of tinea capitis in Western China. METHODS: Children (2-14 years of age) with clinically diagnosed and potassium hydroxide microscopy-confirmed tinea capitis were randomized into three groups: group GRI4 received 4 weeks of griseofulvin; group TBF2 received 2 weeks of terbinafine; and Group TBF4 received 4 weeks of terbinafine. Clinical and mycological evaluations were done in 0, 2, 4, and 8 weeks and 1 year after therapy started. The isolated pathogenic fungi were evaluated for in vitro susceptibility by detecting the minimal inhibitory concentration (MIC) against terbinafine, griseofulvin, itraconazole, and ketoconazole. RESULTS: The clinical effectiveness rate of GRI4, TBF2, and TBF4 were 100% (95% CI-confidence interval: 82-100%), 96.3% (95% CI: 81-100%), and 100%(95% CI: 85-100%), respectively, at week 8 and 100% after 1 year for the 3 groups; clinical cure rates were 84.2%(95% CI: 77-99%), 85.2%(95% CI: 71-98%), and 78.3%(95% CI: 61-95%), respectively, at week 8 and 100% after 1 year for all agents; mycological cure rates were 100%(95% CI: 74-100%), 95.0%(95% CI: 74-100%), and 94.1%(95% CI: 50-93%) at week 8 and 100% after 1 year for the 3 groups. In vitro, all patient-derived cultures were sensitive to the four antifungal agents. CONCLUSION: Data from the clinical trial and in vitro antifungal activity indicated that terbinafine is efficacious and well tolerated in the treatment for Trichophyton infections (T. violaceum; Arthroderma vanbreuseghemii; and T. tonsurans) of the scalp, i.e., a 2- to 4-week course of terbinafine is as effective as a 4-week course of griseofulvin; in fact, a 2-week course of terbinafine is sufficient. Terbinafine is an effective alternative to griseofulvin against tinea capitis of Trichophyton infections.

Two new derivatives of griseofulvin from the mangrove endophytic fungus Nigrospora sp. (strain No. 1403) from Kandelia candel (L.) Druce.

Two new compounds, methyl 3-chloro-6-hydroxy-2-(4-hydroxy-2-methoxy-6-methylphenoxy)-4-methoxybenzoate (1) and (2 S,5' R,E)-7-hydroxy-4,6-dimethoxy-2-(1-methoxy-3-oxo-5-methylhex-1-enyl)-benzofuran-3(2H)-one (2), together with four known compounds, griseofulvin (3), dechlorogriseofulvin (4), bostrycin (5), and deoxybostrycin (6), were isolated from the marine endophytic fungus NIGROSPORA sp. (No. 1403) collected from the South China Sea. The structures were elucidated by spectroscopic methods, 1D, 2D NMR, and HREIMS. Compounds 5 and 6 showed moderate antitumor and moderate antimicrobial activity.

Ethnoveterinary study for antidermatophytic activity of Piper betle, Alpinia galanga and Allium ascalonicum extracts in vitro.

Crude ethanolic extracts of Piper betle leaves (Piperaceae), Alpinia galanga rhizomes (Zingiberaceae) and Allium ascalonicum bulbs (Liliaceae) were tested against selected zoonotic dermatophytes (Microsporum canis, Microsporum gypseum and Trichophyton mentagrophyte) and the yeast-like Candida albicans. A broth dilution method was employed to determine the inhibitory effect of the extracts and compared to those of ketoconazole and griseofulvin. All extracts suppressed the growth of the fungi in a concentration-dependent manner. Among the extracts tested, P. betle exhibited more effective antifungal properties with average IC(50) values ranging from 110.44 to 119.00 microg/ml. Subsequently, 10% Piper betle (Pb) cream was formulated, subjected to physical and microbial limit test and evaluated for antifungal effect. The disc diffusion assay revealed comparable zones of inhibition between discs of Pb cream containing 80 microg P. betle extract and 80 microg ketoconazole against tested fungi at 96 h after incubation. Thereafter, the inhibitory effect of Pb cream markedly decreased and completely lost effectiveness by day 7. In summary, the results supported the traditional wisdom of herbal remedy use and suggested a potential value-addition to agricultural products. It was suggested that the Pb cream has potential therapeutic value for treatment of dermatophytosis. However, clinical testing as well as improving the Pb cream formulation with greater efficacy and duration of action would be of interest and awaits further investigation.

Analysis of Trichophyton rubrum gene expression in response to cytotoxic drugs.

Suppressive subtractive hybridization was used to isolate transcripts specifically upregulated during Trichophyton rubrum exposure to acriflavin, fluconazole, griseofulvin, terbinafine or undecanoic acid. Macro-array dot-blot and sequencing of 132 clones, which correspond to genes differentially expressed after exposition of T. rubrum to at least one of these cytotoxic drugs, revealed 39 unique genes. Of these, 32 have not been previously described in T. rubrum, representing an increase in the number of T. rubrum genes that have been identified. The upregulation of the novel genes encoding a retrotransposon element, a carboxylic ester hydrolase, a copper resistance-associated P-type ATPase, a DNA mismatch repair protein and a NIMA (never in mitosis A) interactive protein was confirmed by Northern blot.

An overview of antifungal drugs and their use for treatment of deep and superficial mycoses in animals.

Fungal infections are often challenging to manage, given the limited numbers of therapeutics and a general lack of applicable clinical literature for their use in a given animal species. This article reviews some of the underlying principles that can affect the therapeutic outcome for a given antifungal, and provides specific information from the literature that is intended to highlight the distinctive properties of the most commonly used antifungals in veterinary medicine to better facilitate their successful application in clinical practice.

[Modern antimycotics. What the treating physician needs to know]. / Moderne Antimykotika. Was der behandelnde Arzt darüber wissen sollte.

The treatment of dermatophytoses is a complex process influenced by the properties of the antimycotic and the causative agent as well as by patient-related factors. Both the minimal inhibition concentration and the drug concentration in the infected tissue influence treatment success. Dermatophytes can be present as arthrospores in the skin, nails or hair. Non-proliferating dermatophytes (arthrospores) are less susceptible to antimycotics than proliferating ones, particularly to antibiotics which act through the inhibition of fungal ergosterol synthesis. Non-proliferating dermatophytes do not synthesize ergosterol, a essential component of fugal cell membranes. Also, dermatophytes accumulating in hollow spaces mostly in the nail plate, cannot be reached by antimycotics. The concentration of terbinafine and itraconazole is very high in sebum. This is of importance in the treatment of dermatophytoses localized to in the stratum corneum and in or around the hair. Preadolescent children do not have functioning sebaceous glands; this explains the difficulties in the treatment of pediatric tinea capitis.

Occurrence of dermatomycoses and in-vitro therapeutic efficacy of three antifungal drugs on the growth of Epidermophyton floccosum.

The occurrence of dermatomycoses and the in-vitro therapeutic efficacy of some antifungal agents on dermatomycotic organisms were investigated. Of the 550 primary school children screened, the incidence was one hundred (18%), 70 were males (representing 20% of the males screened) and 30 females (15% of the females sampled). The differences between male and female prevalence were insignificant. Three species of dermatophytes were isolated and identified. These were Microsporum canis, Trichophyton tonsurans and Epidermophyton floccosum. The antifungal agents tested on E. floccosum were griseofulvin, terbinafine and ketoconazole. They produced different sized zones of inhibition against the growth of E. floccosum. Griseofulvin exhibited a 50% inhibition of growth on E. floccosum at 63.00 mg/L. Terbinafine on the other hand exhibited varying levels of inhibition of growth at varying concentrations, at 0.07 mg/L, terbinafine achieved 46% inhibition of growth on E. floccosum. The drug achieved 100% inhibition of growth on the isolate at 61.81 mg/L. In the case of ketoconazole, 50% inhibition of growth was achieved at 100 mg/L while 100% inhibition of growth was achieved at 200 mg/L. The antifungal effects of the three drugs were confirmed by broth dilution tests where terbinafine was found to be fungistatic on the growth of E. floccosum at concentrations ranging from 0.013-1.700 mg/L and was fungicidal at concentrations ranging from 0.027-1.700 mg/L. Ketoconazole was found to inhibit the growth of E. floccosum at 0.003-1.700 mg/L and was fungicidal at concentrations ranging from 0.027-1.700 mg/L. It however did not succeed in killing the isolate under the same range of concentrations. Griseofulvin exhibited fungistatic effects on the growth of E. floccusum at 0.013-1.700 mg/L. In conclusion, ketoconazole and griseofulvin were found to be fungistatic and not fungicidal while terbinafine was both fungistatic and fungicidal on the pathogen. Terbinafine was found to be the most effective drug in inhibiting E. floccosum.

Antifungal activity of wogonin.

The antifungal activity of the wogonin isolated from Holmskioldia sanguinea Retz was determined on four different fungal organisms. The pure compound wogonin significantly inhibited the growth of Aspergillus niger, Penicillium frequentance, P. notatum and Botrytis cinerea, in a concentration dependent fashion, when tested by turbidity and spore germination methods. The effects produced by the compound were compared with the standard antifungal agent griseofulvin.

Tinea pedis causada por Trichophyton violaceum / Tinea pedis due to Trichophyton violaceum

-La tinea pedis es una dermatofitosis de los pies cuya incidencia ha aumentado fundamentalmente debido a factores ocupacionales y medioambientales diversos. El agente causal más frecuente en los países occidentales es Trichophyton rubrum seguido de T. mentagrophytes var. interdigitale y Epidermophyton floccosum.Se presenta el caso de una niña de 14 años, piragüista federada, con afectación interdigital de los pies consistente en maceración y fisuración, cuyo estudio micológico evidenció Trychophyton violaceum. Este agente es poco frecuente en la tinea pedis. En los países industrializados se presenta, en la mayoría de los casos, como causante de tinea capitis en inmigrantes de áreas donde dicho agente es endémico. Se discuten aspectos diagnósticos y terapéuticos de este proceso (AU)

Preliminary antifungal and cytotoxicity studies of extracts of Ritchiea capparoides var. longipedicellata.

Crude extracts obtained from the leaves, stem bark and roots of Ritchiea capparoides var. longipedicellata were screened for in vitro antifungal activity using the agar tube dilution method. The leaf hexane, leaf methanol, stem bark methanol and root methanol extracts were tested using ten clinical strains of fungi at a concentration of 200 and 400 microg/ml, respectively. At 400 microg/ml, all four extracts inhibited the growth of six of the ten test fungi used in the study. Inhibition of the growth of Aspergillus niger by the extracts was also seen but the activity was low and the leaf hexane and root methanol extracts inhibited the growth of Drechslera rostrata. Only the leaf hexane extract was active against Curvularia lunata, while the growth of Candida albicans was not inhibited by any of the extracts. The inhibition of growth of almost all the microorganisms decreased at 200 microg, griseofulvin was included as a reference compound and methanol as the control. Preliminary cytotoxicity tests were done with the four extracts using the larvae of the brine shrimp, Artemia saline. The extracts were however found to be relatively non-toxic as each extract had an LD50 value greater than 1000 microg/ml.

Oral therapeutic agents in fungal nail disease.

Oral griseofulvin has been the first-line drug in the therapy of dermatophyte onychomycosis for many years. Even when used long-term, it is effective in only about 30% of patients. Ketoconazole is not much more effective than griseofulvin in toenail infections, and there are significant problems with hepatotoxicity. Recently the triazoles, itraconazole and fluconazole, and the allylamine, terbinafine, were introduced and are believed to be potentially suitable for the oral treatment of fungal nail infection. Terbinafine is particularly effective in the treatment of dermatophyte onychomycosis, with a much shorter treatment period than griseofulvin. Cure rates of well over 80% have been noted in fingernail and toenail infection during treatment periods of 6 and 12 weeks, respectively. Itraconazole, 200 mg/day, has been noted in some studies to be similarly effective in the same treatment period. Few studies of fluconazole in nail infection have been carried out. These new agents appear to be safe, and results thus far suggest that they will soon overtake griseofulvin as the drug of choice in the oral therapy of nail infection.

The sensitivity of dermatophytes to griseofulvin.

13 isolates of Trichophyton violaceum and 7 Microsporum langeroni from Zambia and Cameroon were tested in vitro for their sensitivity to griseofulvin. No strain was found resistant. All the 13 T. violaceum were inhibited by 4-8 micrograms/ml while 4 M. langeroni were inhibited by 0.5-1 microgram/ml.