nnd-502 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

Fungal diseases of the nail bed (onychomycosis) and epidermis are recurrent illnesses in the elderly and immunocompromised patients, which have few efficacious treatment options. Current treatment options for onychomycosis are limited to topical agents, laser treatment, and oral antifungals. Previous generations of topical agents were not efficacious, owing to poor penetration of the nail bed. Oral antifungal drugs, such as itraconazole, terbinafine, and fluconazole, not only give better response rates but also inhibit a host of CYP450 enzymes. Oral antifungals can exacerbate drug-drug interactions for patients taking other medications concurrently. Newer topical agents might recognize improved efficacy and provide therapeutic alternatives when the use of oral antifungal agents is contraindicated. Recently, the Food and Drug Administration (FDA) approved efinaconazole and tavaborole for the treatment of onychomycosis. Additionally, the FDA approved luliconazole for the treatment of tinea pedis, tinea cruris, and tinea corporis. This review examines the mechanism of action, spectrum of activity, pharmacokinetics, and clinical trials data and considers the place in therapy for these 3 new antimycotic agents.

Topics: Administration, Topical; Animals; Antifungal Agents; Arthrodermataceae; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatomycoses; Humans; Imidazoles; Microbial Sensitivity Tests; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles

Topics: Acids, Carbocyclic; Benzoxazines; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cephalosporins; Cyclopentanes; Drug Approval; Drug Combinations; Drug Therapy; Glucagon-Like Peptides; Guanidines; Humans; Imidazoles; Immunoglobulin Fc Fragments; Interferon-beta; Isoquinolines; Penicillanic Acid; Polyethylene Glycols; Pyridines; Quinuclidines; Recombinant Fusion Proteins; Tazobactam; Triazoles; United States; United States Food and Drug Administration

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

Members of the Nannizzia gypsea complex are globally the most common geophilic dermatophytes which cause infection in animals and human. Although the susceptibility patterns of anthropophilic or zoophilic dermatophyte species to antifungal agents are well documented, the effectiveness of such drugs against geophilic species have rarely been explored.. This study was aimed to evaluate the in vitro antifungal activity of common and new antifungals against a set of environmental and clinical geophilic dermatophyte isolates.. 108 soil and clinical geophilic isolates from two genera Nannizzia (N. fulva n = 59; N. gypsea n = 43) and Arthroderma (A. quadrifidum n = 4; A. gertleri n = 1; A. tuberculatum n = 1) were included in the study. The in vitro antifungal susceptibility patterns of eight common and new antifungals against the isolates were determined according to broth microdilution method and by CLSI M38-A3 (3rd edition) protocol.. MIC values across all isolates from five species ranged as: luliconazole: 0.0002-0.002 µg/ml, terbinafine: 0.008-0.125 µg/ml, efinaconazole: 0.008-0.125 µg/ml, ciclopirox olamine: 0.03-0.5 µg/ml, itraconazole: 0.125-1 µg/ml, amorolfine hydrochloride: 0.125-4 µg/ml, griseofulvin: 0.25-2 µg/ml and tavaborole: 1-8 µg/ml, respectively.. Luliconazole, terbinafine and efinaconazole exhibited the highest in vitro efficacy, regardless of the dermatophyte species. Further surveillance studies are recommended to confirm the implication of such in vitro data for the clinical recovery rate of dermatophytosis with geophilic species following antifungal therapy.

Topics: Antifungal Agents; Arthrodermataceae; Imidazoles; Itraconazole; Microbial Sensitivity Tests; Terbinafine; Triazoles

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

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

We report a case of contact dermatitis caused by both efinaconazole, a topical triazole antifungal drug, and luliconazole, a topical imidazole antifungal drug. Positive patch test reactions were observed with efinaconazole and luliconazole. A patch test with lanoconazole also elicited a positive reaction. We hypothesized that structural similarity between luliconazole and lanoconazole led to cross-reaction, and that the dithiolane ring common to both drugs or the structure of the vinyl imidazole with a dithiolane ring could be the antigenic determinant. Since efinaconazole and luliconazole have no common structures, patients could be sensitized to both drugs separately. The antigenic determinant of efinaconazole is unknown. However, the chemical formula of ravuconazole, an oral triazole antifungal drug, is similar to that of efinaconazole. Clinicians should carefully consider potential cross-reactivity between these drugs.

Topics: Administration, Topical; Aged; Antifungal Agents; Dermatitis, Contact; Epitopes; Foot Dermatoses; Humans; Imidazoles; Male; Patch Tests; Triazoles

An efficacious period of two topical antifungal drugs was compared in a Trichophyton mentagrophytes-infected onychomycosis model in guinea pigs treated with antifungal drugs prior to infection. Luliconazole 5% (LLCZ) and efinaconazole 10% (EFCZ) test solutions were applied to the animals' nails once daily for 2 weeks followed by a nontreatment period of 2, 4, and 8 weeks. After each nontreatment period, the nails were artificially infected by the fungus. Drug efficacy was quantitatively evaluated by qPCR and histopathological examination of the nails collected following a 4-week post-infection period. The fungal infection was confirmed in the untreated group. Both LLCZ and EFCZ prevented fungal infection in the treated groups with the nontreatment period of 2 weeks. After the nontreatment period of 4 weeks, no infection was observed in the LLCZ-treated group; however, infection into the nail surface and fungal invasion into the nail bed were observed in the EFCZ-treated group. After the nontreatment period of 8 weeks, fungi were found in the nail surface and nail bed in some nails treated with EFCZ; however, no infection was observed in the nail bed of the LLCZ-treated group. The results suggest that LLCZ possesses longer-lasting antifungal effect in nails of the guinea pigs than EFCZ, and that this animal model could be useful for translational research between preclinical and clinical studies to evaluate the pharmacological efficacy of antifungal drugs to treat onychomycosis. This experimentally shown longer-lasting preventive effects of LLCZ could also decrease the likelihoods of onychomycosis recurrence clinically.

Topics: Administration, Topical; Animals; Antifungal Agents; Disease Models, Animal; Guinea Pigs; Imidazoles; Male; Specific Pathogen-Free Organisms; Tinea; Triazoles; Trichophyton

Vulvovaginal candidiasis (VVC) is a common and debilitating long-term illness affecting million women worldwide. This disease is caused mainly by Candida albicans and a lesser extent by other species, including the two phylogenetically closely related pathogens Candida africana and Candida dubliniensis.. In this study, we report detailed molecular epidemiological data about the occurrence of these two pathogenic yeasts in Iranian patients affected by VVC, or its chronic recurrent form (RVVC), and provide, for the first time, data on the antifungal activity of two new drugs, efinaconazole (EFN) and luliconazole (LUL).. A total of 133 vaginal yeast isolates, presumptively identified as C albicans by phenotypic and restriction analysis of rDNA, were further analysed by using a specific molecular method targeting the HWP1 gene. All C africana and C dubliniensis isolates were also tested for their in vitro susceptibility to a panel of modern and classical antifungal drugs.. Based on the molecular results, among 133 germ-tube positive isolates, we identify 119 C albicans (89.47%), 11 C africana (8.27%) and 3 C dubliniensis (2.26%) isolates. C africana and C dubliniensis showed low MIC values for most of the antifungal drugs tested, especially for EFN and LUL, which exhibited a remarkable antifungal activity. High MIC values were observed only for nystatin and terbinafine. Although C albicans remains the most common Candida species recovered from Iranian VVC/RVVC patients, our data show that its prevalence may be slightly overestimated due to the presence of difficult-to-identify closely related yeast, especially C africana.

Topics: Adult; Antifungal Agents; Candida; Candidiasis, Vulvovaginal; DNA, Fungal; Female; Fungal Proteins; Humans; Imidazoles; Iran; Membrane Glycoproteins; Microbial Sensitivity Tests; Middle Aged; Prevalence; Triazoles

In vitro antifungal activity of luliconazole against nondermatophytic moulds causing superficial infections was compared with that of five classes of 12 topical and systemic drugs. The minimum inhibitory concentration (MIC) of the drugs against the genera of Neoscytalidium, Fusarium, Aspergillus, Scedosporium, and Alternaria was measured via modified microdilution method. In results, the nondermatophytic moulds were found to be less susceptible to drugs to which Neoscytalidium spp. and Fusarium spp. were typically drug resistant. However, luliconazole was effective against all the genera tested, including afore-mentioned two species, and had the lowest MICs among the drugs tested.

Topics: Amphotericin B; Antifungal Agents; Clotrimazole; Fluconazole; Fungi; Humans; Imidazoles; Itraconazole; Ketoconazole; Miconazole; Microbial Sensitivity Tests; Morpholines; Sequence Analysis, DNA; Terbinafine; Triazoles; Voriconazole

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

The

Topics: Adult; Antifungal Agents; Ascomycota; Child, Preschool; Drug Resistance, Fungal; Female; Humans; Imidazoles; Male; Microbial Sensitivity Tests; Middle Aged; Mycoses; Triazoles; Yeasts; Young Adult

 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

The minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of luliconazole against Trichophyton rubrum (14 strains) and Trichophyton mentagrophytes (14 strains), which are the most common cause of tinea, were compared with those of 6 topical antifungal drugs of lanoconazole, bifonazole, efinaconazole, liranaftate, naftifine and terbinafine.　Luliconazole showed the most potent antifungal activity (MIC90 =0.00098 μg/ml and MFC90 =0.0078 μg/ml) among the compounds tested against the two species. Efinaconazole and bifonazole, the drug of azole-class, showed a large MFC/MIC ratio. On the other hand, these ratios of luliconazole and lanoconazole were as small as those of liranaftate, naftifine and terbinafine which are thought to possess fungicidal mechanism. These results suggest that luliconazole possesses fungicidal activity against both species of Trichophyton.　In this study, we found that luliconazole had the most potent antifungal activity among the major topical antimycotics used in Japan and the US. Luliconazole would be the best-in-class drug for dermatophytosis in clinics.

Topics: Allylamine; Antifungal Agents; Drug Resistance, Fungal; Imidazoles; Microbial Sensitivity Tests; Naphthalenes; Pyridines; Terbinafine; Thiocarbamates; Triazoles; 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