nnd-502 and Onychomycosis

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

Luliconazole is a novel, broad-spectrum, imidazole antifungal under development in the USA as a treatment for dermatophytic skin and nail infections. In vitro, luliconazole is one of the most potent antifungal agents against filamentous fungi including dermatophytes. Luliconazole has been formulated in a 10% solution with unique molecular properties, which allow it to penetrate the nail plate and rapidly achieve fungicidal levels in the nail unit. These properties make luliconazole a potent compound in the treatment of onychomycosis. This article reviews the development of luliconazole solution, 10% its molecular properties, preclinical and clinical data and its future perspectives for the treatment of fungal infections.

Topics: Administration, Topical; Antifungal Agents; Foot Dermatoses; Humans; Imidazoles; Onychomycosis; Pharmaceutical Solutions

Approximately 20-25% of the population worldwide is affected by superficial cutaneous mycoses (SCM). SCM are cutaneous fungal infections with a wide array of systemic and topical treatment options. However, successful therapeutic outcomes are limited by patient non-adherence, medication side effects, potential drug interactions, antifungal resistance and disease recurrence. Advances in formulation technology have allowed for the development of more effective and safer therapies. In this article we will review several new and emerging pharmacotherapeutics for onychomycosis and tinea pedis.

Topics: Allylamine; Antifungal Agents; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Education, Medical, Continuing; Humans; Imidazoles; Itraconazole; Onychomycosis; Tinea Pedis; Triazoles

Onychomycosis is a highly prevalent and intractable disease. The first-line treatment agents are oral preparations, but an effective topical medication has long been desired. The objective was to investigate the efficacy and safety of luliconazole 5% nail solution, an imidazole antifungal agent, for the treatment of patients with onychomycosis. A multicenter, double-blind, randomized phase III study was conducted in Japanese patients with distal lateral subungual onychomycosis affecting the great toenails, with 20-50% clinical involvement. Patients were randomized (2:1) to luliconazole or vehicle once daily for 48 weeks. The primary end-point was the complete cure rate (clinical cure [0% clinical involvement of the nail] plus mycological cure [negative results on direct microscopy]). The adverse event incidence was monitored to evaluate safety. The complete cure rate significantly favored luliconazole (14.9%, 29/194 subjects) versus vehicle (5.1%, 5/99) (P = 0.012). Similarly, the negative direct microscopy rate was significantly higher with luliconazole (45.4%, 79/174) than with vehicle (31.2%, 29/93) (P = 0.026). There were no serious adverse drug reactions. We conclude that once daily topical luliconazole 5% nail solution demonstrated clinical efficacy and was confirmed to be well tolerated.

Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Double-Blind Method; Female; Foot Dermatoses; Humans; Imidazoles; Japan; Male; Microscopy; Middle Aged; Onychomycosis; Pharmaceutical Solutions; Tinea; Treatment Outcome; Trichophyton; Young Adult

To evaluate the efficacy of fractional carbon dioxide (CO2) laser combined with luliconazole 1% cream for the treatment of onychomycosis and to compare it with that of fractional CO2 laser alone.. This was a randomized, parallel group, 2-arm, positive-controlled, single-center, superiority trial with a 1:2 allocation ratio. Sixty patients with clinical and mycological diagnosis of onychomycosis were enrolled from the Dermatology Department of the First Affiliated Hospital of Nanjing Medical University in Nanjing, China from March 2015 to May 2015. Patients were randomized following simple randomization procedures (computerized random number generator) into 2 groups; L group only received 12 sessions of laser treatment at 2-week interval for 6 months, while L + D group received 12 sessions of laser treatment at 2-week interval combined with luliconazole 1% cream once daily for 6 months. This was not a blind trial. The main outcome measures were the clinical efficacy rate (CER) assessed from the percentage of fully and >60% normal-appearing nails and the mycological clearance rate (MCR) assessed from the percentage of nails with negative fungal microscopy. There were no changes to trial outcome measures after the trial commenced.. A total of 60 patients (N = 233 nails) completed treatments and follow-up, and were randomized and divided into 2 groups: L group (31 patients, N = 108 nails) and L + D group (29 patients, N = 115 nails). The CER and MCR of L + D group were 69.6% and 57.4%, respectively. L + D group showed significantly higher CER (69.6% vs 50.9%; χ = 8.1, P = 0.004) and MCR (57.4% vs 38.9%; χ = 7.6, P = 0.006) compared with those in L group. Some patients experienced mild pain during laser treatment, but there was no bleeding or oozing during or after treatment. There were no adverse effects reported during the observation period.. Fractional CO2 laser treatment combined with 1% luliconazole cream for 6 months was an effective and safe method for the treatment of onychomycosis, and had a higher efficacy than fractional CO2 laser treatment alone.

Topics: Adult; Aged; Antifungal Agents; Combined Modality Therapy; Dosage Forms; Female; Humans; Imidazoles; Lasers, Gas; Male; Middle Aged; Onychomycosis; Treatment Outcome; Young Adult

The study objective was to evaluate the safety, tolerability, systemic exposure, and pharmacokinetics (PK) of 10% luliconazole solution (luliconazole) when topically applied once daily to all 10 toenails and periungual areas in patients with moderate to severe distal subungual onychomycosis. In this single-center, open-label study, 24 patients applied 20 mg/ml of luliconazole (twice the clinical dose) for 29 days with a 7-day follow-up. Complete PK profiles were determined on days 1, 8, 15, and 29. Safety/tolerability assessments included application site reactions, adverse events, vital signs, clinical laboratory findings, and electrocardiograms. Mean luliconazole plasma concentrations remained around the lower limit of quantitation (0.05 ng/ml) and were comparable on days 8, 15, and 29 (range, 0.063 to 0.090 ng/ml), suggesting steady state occurred by day 8. Every patient had undetectable plasma luliconazole levels for at least 11% of the time points, and 12 of the 24 patients had undetectable levels for at least 70% of the time points. The maximum plasma concentration of luliconazole (C(max)) observed in any patient was 0.314 ng/ml and the maximum area under the concentration-time curve from 0 to 24 h (AUC0-24) was 4.34 ng · h/ml. Five patients (21%) had measureable luliconazole levels in the plasma 7 days after the last dose. The median concentration of luliconazole in the nail at this time point was 34.65 mg/g (from 42 of 48 collected toenail samples). There was one mild incidence of skin erythema on day 5 that resolved on day 8, there were no reports of drug-induced systemic side effects, and there was no evidence of QT prolongation. Luliconazole, when applied once daily to all 10 fungus-infected toenails for 29 days, is generally safe and well tolerated and results in significant accumulation of drug in the nail. Systemic exposure is very low, with no evidence of drug accumulation.

Topics: Adult; Antifungal Agents; Area Under Curve; Drug Administration Schedule; Female; Humans; Imidazoles; Male; Middle Aged; Nails; Onychomycosis; Pharmaceutical Solutions; Treatment Outcome

A woman in her 70s had onychomycosis that was treated with topical luliconazole solution. Her nails changed color to yellow due to the treatment and exposure to sunlight. Avoidance of sunlight and continuous application of luliconazole resolved the discoloration and were effective for the treatment of onychomycosis one year after the first visit.

Topics: Administration, Topical; Antifungal Agents; Female; Humans; Imidazoles; Nails; Onychomycosis

To be effective against onychomycosis, topically applied drugs have to reach the infection site at an effective concentration to exert antifungal activity against the parasitic form of dermatophytes. We established a novel in vitro method for predicting drug efficacy at the infection site and verified the method by comparing the efficacy of two azole class topical anti-onychomycosis drugs. To predict drug efficacy in the nail plate, a human nail permeability test was conducted and the activities of the free-drugs in the upper, middle, and lowest layers of the nail plate were determined by measuring the growth inhibitory zone. Efinaconazole permeated the nail more efficiently than luliconazole, and the amount of efinaconazole in the middle and lowest layers was higher compared with that of luliconazole. Efinaconazole demonstrated antifungal activities at the concentrations in all of the nail layers, whereas luliconazole was only active at the concentrations in the upper and middle layers. The results could be explained by differences in their affinity for keratin and nail permeability. The established method enables the evaluation of nail permeability and anti-arthrospore activity of free-drugs in the nail plate to predict drug efficacy. This method will be useful for new topical drug development.

Topics: Administration, Topical; Antifungal Agents; Humans; Imidazoles; Nails; Onychomycosis; Triazoles

Onychomycosis is the most common fungal infection of the nail affecting the skin under the fingertips and the toes. Currently, available therapy for onychomycosis includes oral and topical therapies, either alone or in combination. Oral antifungal medication has been associated with poor drug bioavailability and potential gastrointestinal and systemic side effects. The objective of this study was to prepare and evaluate the luliconazole nail lacquer (LCZ-NL) for the effective treatment of onychomycosis. In the current work, LCZ-NL was formulated in combination with penetration enhancers to overcome poor penetration. A 3

Topics: Administration, Topical; Antifungal Agents; Humans; Imidazoles; Lacquer; Nails; Onychomycosis; Solvents

Luliconazole, recently launched in Japan, is a novel topical imidazole antifungal agent for the treatment of onychomycosis. Using in vitro onychomycosis model, the effect of luliconazole on the morphology of the growing hyphae of Trichophyton mentagrophytes was investigated by scanning electron microscopy (SEM). The model was produced by placing human nail pieces on an agar medium seeded with conidia of T. mentagrophytes. After incubating the agar medium for 3 days, luliconazole was applied to the surface of the nail in which hyphal growth was recognized, then cultured for up to 24 h. The initial change after treatment with the drug was the formation of fine wrinkles on the surface of the hyphae, eventually, the hyphae were flattened, and after that, no hyphal growth was observed. On the other hand, when the nails were pretreated with luliconazole for 1 h, no hyphal growth was observed even after culturing for 24 h. This study suggests that luliconazole has a strong antifungal activity by inhibiting the ability of fungi to grow and the drug has both excellent nail permeation and retention properties.

Topics: Agar; Antifungal Agents; Culture Media; Humans; Hyphae; Imidazoles; Onychomycosis

Development of new topical drugs requires an animal onychomycosis model that can predict the drug efficacy against moderate to severe human onychomycosis because the severity of onychomycosis varies and affects the drug efficacy. This study established a non-immunosuppressive guinea pig tinea unguium model under 8-week infection condition in addition to a previously reported model under 4-week infection condition. In the tinea unguium model, most fungi were tightly present in the arthrospore form, like in human onychomycosis. The topical formulations of efinaconazole and luliconazole, two azole class anti-onychomycosis drugs, were evaluated for their efficacy in these models. In the untreated group, the nail fungal burden in the 8-week model was higher than that in the 4-week model and the stronger infection intensity affected the efficacy of the drugs, suggesting that the 8-week model was more severe. The 90% efficacy rate (42%) of luliconazole in the 8-week model was significantly lowered than that (83%) in the 4-week model, and its 99% efficacy rates were 0% in both models. Conversely, the 90% and 99% efficacy rates of efinaconazole (92% and 50% in the 4-week model, and 75% and 25% in the 8-week model, respectively) were not significantly different between the two infection durations. In addition, efinaconazole was more effective than luliconazole in reducing the nail fungal burden. Considering the relevance of clinical reports of the effectiveness of efinaconazole on severe onychomycosis, the new severe tinea unguium model would predict drug efficacy against moderate to severe onychomycosis.

Topics: Administration, Topical; Animals; Antifungal Agents; Disease Models, Animal; Guinea Pigs; Humans; Onychomycosis

Wood's lamp was demonstrated to be useful in three cases of dermatophytoma treated during clinical dermatological practice. Clinical signs of onychomycosis are longitudinal yellow and white striae on the nail plate and are diagnosed by KOH direct microscopic examination. For its treatment, surgical debridement is recommended. Usefulness of the Wood's lamp for diagnosis of tinea capitis caused by Microsporum canis is standard. In the first and second cases, we used Wood's lamp (Woody™) to make a clear margin for debridement of onychomycosis. In the third case, onychomycosis was unsuccessfully treated using topical 5% luliconazole nail solution for 1 year and 10 months with yellow nail discoloration. Under Wood's lamp, we were able to distinguish luliconazole crystal staining from onychomycosis. This method is simple and quick, and useful for nail observation in dermatology clinics.

Topics: Aged; Dermatology; Humans; Imidazoles; Male; Microsporum; Middle Aged; Nails; Onychomycosis; Time Factors

Many clinicians prefer to treat onychomycosis systemically. However, systemic therapy may not be suitable for all onychomycosis patients due to drug interactions, side effects of oral medications, or comorbidities. Two topical agents (efinaconazole 10% in 2014 and luliconazole 5% in 2016) have recently been approved for treatment of onychomycosis in Japan. We investigated the efficacy of these topical agents at Teikyo University Mizonokuchi Hospital, Kanagawa, Japan. We conducted a retrospective survey among patients diagnosed with onychomycosis at our outpatient clinic and had been treated with either efinaconazole 10% solution or luliconazole 5% solution. Prior to commencement of treatment, the disease severity was evaluated using the Scoring Clinical Index for Onychomycosis (SCIO). Furthermore, the efficacies of these agents were evaluated using turbidity scoring at each visit to our outpatient clinic. Sixty-two patients (33 men, 29 women) applied efinaconazole 10% solution, and 72 patients (35 men, 37 women) applied luliconazole 5% solution. The mean SCIO scores were 18.1 and 17.4, respectively, and the mean 5-grade evaluation scores were 3.5 and 3.4, respectively. Complete cure rates were 40.3% (25/62) and 33.3% (24/72), respectively. The mean durations of treatment were 15.4 months and 11.9 months, respectively. There were no serious side effects in either treatment group. There were no significant differences between the two agents in improvement scores as assessed by the Tukey's test. Thus, efinaconazole 10% and luliconazole 5% topical solutions were effective for the treatment of onychomycosis. These topical agents may become important treatment options for this indication.

Topics: Administration, Topical; Adult; Aged; Female; Humans; Imidazoles; Male; Middle Aged; Onychomycosis; Retrospective Studies; Solutions; Treatment Outcome; Triazoles

Topics: Antifungal Agents; Drug Compounding; Drug Delivery Systems; Humans; Hydrophobic and Hydrophilic Interactions; Imidazoles; Lacquer; Onychomycosis

 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

To clarify the character of luliconazole nail solution we have developed, we investigated luliconazole distribution and antifungal activity in nail plate. An in vitro permeation study which measured luliconazole concentration of sliced nail in the transverse direction after treatment of luliconazole nail solution was conducted to investigate for concentration dependency and the influences of nail thickness and treatment duration. When 0.2, 1, 3, 5, and 7.5% luliconazole nail solutions were used, luliconazole was detected in the all the layers of nail and there was a concentration gradient from the dorsal side to deep nail layers. The luliconazole concentration was almost same after 14-day treatment with 5% luliconazole nail solution when using nails of different thicknesses. And we confirmed that concentration of luliconazole into the nail was increased depending on the treatment duration. In zone of inhibition test after 14-day treatment, 5% luliconazole nail solution showed statistically high formation rate of zones of inhibition compared to 8% ciclopirox nail lacquer. Above all, these data suggested that 5% luliconazole nail solution has the potential to show high therapeutic effect for onychomycosis.

Topics: Administration, Topical; Antifungal Agents; Ciclopirox; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Humans; Imidazoles; Microbial Sensitivity Tests; Nails; Onychomycosis; Permeability; Pyridones; Solutions; Time Factors; Trichophyton

We evaluated luliconazole nail solution, originally generated formulation, for the topical treatment of onychomycosis by two infection models. First, a suspension of Trichophyton mentagrophytes was dropped onto the ventral layer of human nail plate and these nails were set in Franz diffusion cells. After 9-day culture, luliconazole nail solutions (1, 3, and 5%) were applied to the dorsal surface of the nails once a day for 7 days. After application, fungal viability was assessed by measuring the ATP contents of the samples. The dose-dependent efficacy was confirmed, with 3% and 5% luliconazole nail solutions producing significantly lower ATP levels at 7-day treatment. When 3% and 5% luliconazole nail solutions were evaluated in a rabbit model of onychomycosis, both concentrations completely inhibited the recovery of fungi on culture after 4-week treatment. We therefore think these results indicate that 5% luliconazole nail solution is sufficiently potent for treatment of onychomycosis.

Topics: Adenosine Triphosphate; Administration, Topical; Animals; Antifungal Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Humans; Imidazoles; Male; Onychomycosis; Rabbits; Solutions; Treatment Outcome; Trichophyton

Luliconazole (LLCZ), an imidazole derivative with a broad spectrum of potent antifungal activity especially for T. rubrum and T. mentagrophytes, is under development as a new drug for treatment of tinea unguium.　It is well known that curative effect of an antifungal agent in dermatophytosis is affected by the pharmacokinetics of an agent at the infection loci as well as its antifungal activity, but there is no report about the affinity of LLCZ to nail keratin. We studied LLCZ affinity to keratin powder prepared from healthy human nail and porcine hoof. The LLCZ adsorbed to keratin preparations was washed with phosphate buffer, and its concentration in the buffer supernatant was measured by HPLC. Antifungal titer of the supernatant was also biologically confirmed by disk diffusion assay. Adsorption rate of LLCZ was 80% or more, and LLCZ was gradually liberated into washing buffer. Cumulative liberation rate in 10 times repeated washing against initially adsorbed drug amount was 47.4% for keratin from human nail and was either 52.5% or 50.8% (depending on the LLCZ concentration) for keratin from porcine hoof. The supernatant showed antifungal potential to T. rubrum. These results indicate that LLCZ applied to the nail surface is fully adsorbed to nail keratin and gradually liberated from it. The nail keratin could function as drug reservoir to supply biologically active LLCZ to the nail tissue region of infection loci. The LLCZ delivered to the loci would exert its antifungal potential on tinea unguium. This study also suggests the versatility of porcine hoof powder as an alternative to human nail keratin preparation for non-clinical study.

Topics: Animals; Antifungal Agents; Hoof and Claw; Humans; Imidazoles; Keratins; Nails; Onychomycosis; Protein Binding; Swine; Trichophyton

Onychomycosis and tinea pedis are common fungal infections affecting the nails and feet, respectively. Two newly approved topical agents for onychomycosis are efinaconazole and tavaborole, both of which have demonstrated respectable cure rates in clinical studies. For tinea pedis, naftifine 2% and luliconazole 1% are new agents, both administered for relatively short courses, that may foster greater adherence Semin Cutan Med Surg 35(supp6):S110-S113.

Topics: Administration, Cutaneous; Antifungal Agents; Humans; Imidazoles; Onychomycosis; Recurrence; Tinea; Tinea Pedis; Triazoles

Two topical therapeutic agents were approved in Japan from 2015 to 2016, adding new options for onychomycosis therapy in the clinical field. In order to confirm the differences of formulation properties and nail pharmacokinetics between 5% luliconazole solution and 10% efinaconazole solution, drug concentration and antifungal activity in the nail were measured after topical treatment using human nail plates. In the in vitro permeation study, concentration of each drug was measured in the transversely sliced nail after single treatment with the two topical therapeutic agents. The results showed that concentration of luliconazole is higher than that of efinaconazole at all nail layers, differing by 1.7-8.4 times at each measurement point. Next, we examined antifungal activities of each drug in sliced nail after 14-day topical treatment. Mean rates of formation of inhibition zones for 5% luliconazole solution and 10% efinaconazole solution were 71.0% and 12.6%, respectively, and were statistically different. These results show that the two topical therapeutic agents have different properties, and suggest that 5% luliconazole solution has good nail permeation and retention characteristics. Moreover, luliconazole was found to retain enough antifungal activity in the nail plate against Trichophyton spp. after treatment with the topical agent.

Topics: Administration, Topical; Antifungal Agents; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Fungal; Humans; Imidazoles; In Vitro Techniques; Nails; Onychomycosis; Solutions; Triazoles; Trichophyton

The in vitro activities of luliconazole, amorolfine, ciclopirox, and terbinafine were determined against 320 dermatophyte isolates from large toenails of onychomycosis patients enrolled into an ongoing phase 2b/3 clinical study. The geometric mean MIC for luliconazole was 0.00022 μg/ml against all isolates, compared to 0.0194 to 0.3107 μg/ml for the three other agents. The in vitro potency of luliconazole was maintained regardless of the dermatophyte species.

Topics: Antifungal Agents; Arthrodermataceae; Ciclopirox; Dermatomycoses; Humans; Imidazoles; Microbial Sensitivity Tests; Morpholines; Naphthalenes; Onychomycosis; Pyridones; Terbinafine