bromochloroacetic-acid and efinaconazole

Tinea pedis and tinea unguium are the most common dermatophytoses seen in the daily practice of dermatology. According to a report in Japan Foot Week 2006, it is estimated that about 1 in 5 Japanese have tinea pedis and that about 1 in 10 have tinea unguium. Thus far, use of oral antifungal agents has been the first-line therapy for onychomycosis. Many patients with onychomycosis, however, are elderly and have concomitant diseases as well as liver function disorder. Moreover, oral medications are reportedly associated with risks of impaired liver function and interactions. Due to such risks, therefore, treatment with topical agents is the only applicable therapy for most patients with onychomycosis. Recently, two topical agents (efinaconazole in 2014 and luliconazole in 2016) have been approved for the treatment of onychomycosis in Japan. Efinaconazole 10% solution is a triazole antifungal drug developed in Japan. Due to its low keratin affinity, efinaconazole shows high transungual penetration into nails and retains a high antifungal activity in the nail plate and the nail bed. Luliconazole 5% solution is an imidazole antifungal agent that has high keratin affinity. Luliconazole has also been shown in vitro to permeate from the superficial to the deep layers of the nail and to achieve concentrations above the MIC in all layers of the nail. Both efinaconazole 10% solution and luliconazole 5% solution have high antifungal activities for Trichophyton species. These two topical agents, therefore, have certainly increased treatment options for onychomycosis in the daily practice of dermatology.

Topics: Administration, Topical; Antifungal Agents; Drug Resistance, Fungal; Humans; Imidazoles; Keratins; Nails; Onychomycosis; Solutions; Triazoles; Trichophyton

Onychomycosis is a nail fungal infection, mostly caused by dermatophytes. The treatment efficacy is impaired by difficulties of reaching effective drug levels at the site of infection; frequent relapses occur after cessation of antifungal therapy. The aim of the study was to compare two commercial products containing ciclopirox or efinaconazole for antimycotic activity and antifungal drug resistance. A study of permeation and penetration through bovine hoof membranes, as a nail model, was performed to evaluate the antimycotic activity of permeates against clinical isolates of selected fungi, and the frequency of spontaneous

Topics: Animals; Antifungal Agents; Biological Transport; Cattle; Ciclopirox; Drug Resistance, Fungal; Hoof and Claw; Humans; Keratins; Microbial Sensitivity Tests; Microtomy; Models, Biological; Mutation; Nails; Permeability; Protein Binding; Tinea; Triazoles; Trichophyton

 Affinity of Luliconazole (LLCZ), an antifungal drug used for topical treatment of onychomycosis in Japan, to nail keratin was demonstrated. Efinaconazole (EFCZ) was used as a reference drug. Drugs at fixed concentrations were added to 4 ml of buffer solution containing 40 mg of nail keratin powder prepared from healthy volunteers or from tinea unguium patients. The mixtures were shaken at 37℃, and adsorption and desorption rates of the drug in nail keratin were measured. Theoretical analysis using the Freundlich adsorption isotherm was applied to eliminate effects of testing conditions on the results. Results showed that compared with EFCZ, LLCZ exhibited high adsorption rates and low desorption rates in nail keratins. These results were verified by Freundlich analysis, in which adsorption coefficient (K

Topics: Humans; Imidazoles; Keratins; Nails; Onychomycosis; Triazoles

We hypothesised that Hansen Solubility Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) determine the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/solubility in organic liquids, (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of experimentally-determined affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match experimental reports of these drugs' affinities to keratin. We therefore propose that drug and nail Hansen Solubility Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.

Topics: Adolescent; Adult; Antifungal Agents; Ciclopirox; Drug Interactions; Female; Humans; Keratins; Male; Middle Aged; Morpholines; Nail Diseases; Nails; Naphthalenes; Onychomycosis; Pharmaceutical Preparations; Pyridones; Solubility; Terbinafine; Triazoles; Young Adult

Onychomycosis is a common fungal nail disease that is difficult to treat topically due to the deep location of the infection under the densely keratinized nail plate. Keratin affinity of topical drugs is an important physicochemical property impacting therapeutic efficacy. To be effective, topical drugs must penetrate the nail bed and retain their antifungal activity within the nail matrix, both of which are adversely affected by keratin binding. We investigated these properties for efinaconazole, a new topical antifungal for onychomycosis, compared with those of the existing topical drugs ciclopirox and amorolfine. The efinaconazole free-drug concentration in keratin suspensions was 14.3%, significantly higher than the concentrations of ciclopirox and amorolfine, which were 0.7% and 1.9%, respectively (P < 0.001). Efinaconazole was released from keratin at a higher proportion than in the reference drugs, with about half of the remaining keratin-bound efinaconazole removed after washing. In single-dose in vitro studies, efinaconazole penetrated full-thickness human nails into the receptor phase and also inhibited the growth of Trichophyton rubrum under the nail. In the presence of keratin, efinaconazole exhibited fungicidal activity against Trichophyton mentagrophytes comparable to that of amorolfine and superior to that of ciclopirox. In a guinea pig onychomycosis model with T. mentagrophytes infection, an efinaconazole solution significantly decreased nail fungal burden compared to that of ciclopirox and amorolfine lacquers (P < 0.01). These results suggest that the high nail permeability of efinaconazole and its potent fungicidal activity in the presence of keratin are related to its low keratin affinity, which may contribute to its efficacy in onychomycosis.

Topics: Administration, Topical; Animals; Antifungal Agents; Guinea Pigs; Humans; In Vitro Techniques; Keratins; Microbial Sensitivity Tests; Nails; Onychomycosis; Tinea; Triazoles; Trichophyton

The therapeutic efficacy of KP-103, a triazole derivative, for 10 guinea pigs with interdigital tinea pedis or tinea corporis was investigated. Topical KP-103 solution (0.25 to 1%) was dose-dependently effective in treating both dermatophytoses. A 1% KP-103-treatment rendered all infected skins culture-negative on day-2 posttreatment. A high negative-culture rate was obtained with 1% solutions of butenafine and lanoconazole but not with 1% neticonazole solution. The follow up study performed on day-30 and day-9 posttreatment demonstrated that the relapse rates for 1% KP-103-treated animals with tinea pedis and for those with tinea corporis were 20 and 30%, respectively, and that these values were the same as those for 1% butenafine-treated animals, but lower than those for 1% lanoconazole-treated animals (55 and 80%, respectively). When a single dose of 1% KP-103 was applied to the back skin 48 hr before fungal inoculation, 9 of the 10 animals were protected from the dermatophytosis, suggesting that active KP-103 is retained in skin tissue for at least 48 hr after dosing. Moreover, it was suggested that KP-103 retains a high activity in the horny layer because of its lower keratin-affinity. The effectiveness of KP-103 against dermatophytoses may be due to the favorable pharmacokinetic properties in the skin tissues, together with its potent antifungal activity.

Topics: Animals; Antibiotic Prophylaxis; Antifungal Agents; Aspergillus flavus; Disease Models, Animal; Drug Evaluation, Preclinical; Guinea Pigs; Keratins; Male; Microbial Sensitivity Tests; Secondary Prevention; Tinea; Tinea Pedis; Toes; Treatment Outcome; Triazoles; Trichophyton