nnd-502 and Dermatomycoses

Luliconazole is the first and only anti-fungal agent approved for the short-term treatment of superficial fungal infections. However, commercially available conventional topical dermal drug delivery cargo of luliconazole is associated with certain limitations, like lower skin permeation and shorter skin retention of drug. Therefore, the present review is an attempt to unravel the penetration hurdles in luliconazole topical dermal drug delivery. Moreover, we have also summarized the activity of functional nanomaterials-based drug delivery systems employed by the scientific fraternity to improve luliconazole efficacy in superficial fungal infections on a case-to-case basis. In addition, efforts have also been made to unveil the critically acclaimed mechanism of action of luliconazole against fungal cells. Under the framework of future prospects, we have analyzed the combination of luliconazole with isoquercetin using the in-silico docking technique for offering synergistic antifungal activity. Isoquercetin exhibited a good affinity for superoxide dismutase (SOD), a fungal target, owing to the formation of hydrogen bonds with Glu132, Glu133, and Arg143, in addition to a few hydrophobic interactions. On the other hand, luliconazole inhibited lanosterol-14α-demethylase, and consequently blocked ergosterol. In addition, nanotechnology and artificial neural network (ANN) derived integrated drug delivery systems may also be explored for augmenting the luliconazole therapeutic efficacy in topical fungal infections. Synergy of ANN models along with topical nanoscaled drug delivery may help to achieve critical quality attributes (CQA), leading to commercial success of luliconazole.

Topics: Antifungal Agents; Dermatomycoses; Drug Delivery Systems; Humans; Imidazoles; Nanostructures

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

Dermatomycoses of zoophilic origin, especially those caused by Trichophyton mentagrophytes, often pose considerable therapeutic problems. This is reflected in the growing number of strains of this species with resistance to terbinafine caused by a mutation in the squalene epoxidase (SQLE) gene. Therefore, it is reasonable to look for alternative therapies to the commonly used terbinafine. The aim of the present study was to assess the in vivo effectiveness of topical therapy with luliconazole or terbinafine 1% cream.. Therapeutic efficacy was assessed using direct examination in KOH with DMSO, qPCR analysis with pan-dermatophyte primers and culturing. Moreover, in vitro susceptibility tests for luliconazole and terbinafine were performed.. The results demonstrated significantly higher antifungal activity of luliconazole than terbinafine against dermatomycoses caused by T. mentagrophytes. The geometric mean of the MIC value for luliconazole against all T. mentagrophytes strains was 0.002 μg/ml, while this value for terbinafine was 0.004 μg/ml. In all studied cases, 28-day local therapy with luliconazole contributed to complete eradication of the aetiological agent of infection.. Given the increasingly frequent reports of difficult-to-treat dermatophytoses caused by zoophilic terbinafine-resistant strains, the 1% luliconazole cream can be alternative solution in topical therapy.

Topics: Administration, Topical; Antifungal Agents; Arthrodermataceae; Dermatomycoses; Drug Resistance, Fungal; Genotype; Humans; Imidazoles; Microbial Sensitivity Tests; Terbinafine

Dermatophytes are a group of keratinophilic fungi that invade and infect the keratinized tissues and cause dermatophytosis. We investigated effectiveness of novel triazole (luliconazole and lanaconazole) in comparison with available antifungal agents against dermatophyte species isolated from patients with tinea pedis.. A total of 60 dermatophytes species were isolated from the patients with tinea pedis. Identification of species was done by DNA sequencing of the ITS1-5.8S rDNA-ITS2 rDNA region. In vitro antifungal susceptibility testing with luliconazole and lanaconazole and available antifungal agent was done in accordance with the Clinical and Laboratory Standards Institute, M38-A2 document.. In all investigated isolates, luliconazole had the lowest minimum inhibitory concentration (MIC) (MIC range=0.0005-0.004μg/mL), while fluconazole (MIC range=0.4-64μg/mL) had the highest MICs. Geometric mean MIC was the lowest for luliconazole (0.0008μg/mL), followed by lanoconazole (0.003μg/mL), terbinafine (0.019μg/mL), itraconazole (0.085 μg/mL), ketoconazole (0.089μg/mL), econazole (0.097μg/mL), griseofulvin (0.351 μg/mL), voriconazole (0.583μg/mL) and fluconazole (11.58μg/mL).. The novel triazoles showed potent activity against dermatophytes and promising candidates for the treatment of tinea pedis caused by Trichophyton and Epidermophyton species. However, further studies are warranted to determine the clinical implications of these investigations.

Topics: Antifungal Agents; Arthrodermataceae; Dermatomycoses; Fluconazole; Griseofulvin; Humans; Imidazoles; Itraconazole; Ketoconazole; Microbial Sensitivity Tests; Terbinafine; Tinea; Tinea Pedis; Triazoles; Trichophyton; Voriconazole

Topics: Administration, Cutaneous; Aged; Animals; Antifungal Agents; Biopsy; Cats; Dermatomycoses; Female; Humans; Imidazoles; Microsporum; Pets; Skin; Soil Microbiology; Treatment Outcome

In vitro susceptibilities of 100 clinical dermatophyte isolates belonging to five species from Iran toward lanoconazole and luliconazole were compared with ten other antifungal agents including econazole, itraconazole, miconazole, fluconazole, griseofulvin, butenafine, terbinafine, caspofungin, anidulafungin and tolnaftate. MIC and MEC values were analyzed according to CLSI M38-A2 document. The isolates were previously identified to the species level using PCR-RFLP on ITS rDNA region. The range of luliconazole and lanoconazole minimum inhibitory concentrations (MICs) was 0.016-0.032 and 0.063-1 μg/ml, respectively for dermatophyte species. Luliconazole and lanoconazole revealed potent activity against all dermatophyte isolates. Anidulafungin, caspofungin, and luliconazole showed the best activity with the lowest geometric mean 0.01, 0.016, and 0.018 μg/ml, respectively, followed by tolnaftate (0.06 μg/ml), terbinafine (0.07 μg/ml), itraconazole (0.183 μg/ml), butenafine (0.188 μg/ml), econazole (0.20 μg/ml), lanoconazole (0.24 μg/ml), griseofulvin (1.28 μg/ml), miconazole (2.34 μg/ml) and fluconazole (15.34 μg/ml). The current study demonstrated luliconazole and lanoconazole displayed excellent activity against all dermatophyte isolates, although the majority of dermatophyte isolates showed low susceptibility to griseofulvin and very low to miconazole, and fluconazole.

Topics: Antifungal Agents; Arthrodermataceae; Dermatomycoses; DNA, Ribosomal Spacer; Humans; Imidazoles; Iran; Microbial Sensitivity Tests; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length

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

The in vivo efficacy of terbinafine was compared to lanoconazole and luliconazole in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea pig model. Topical antifungal treatment commenced three days post-infection, and each agent was applied once daily for seven consecutive days. Upon completion of the treatment period, evaluations of clinical and mycological efficacies were performed, as was scanning electron microscopy (SEM) analyses. Data showed that while all tested antifungals demonstrated significant mycological efficacy in terms of eradicating the fungi over untreated control, terbinafine and luliconazole showed superior clinical efficacy compared to lanoconazole (P-values < 0.001 & 0.003, respectively). Terbinafine demonstrated the highest clinical percent efficacy. SEM analysis revealed hairs from terbinafine and lanoconazole-treated animals had near complete clearance of fungi, while samples from luliconazole-treated animals were covered with debris and few conidia. This study demonstrates that, in general, terbinafine possessed similar efficacy to lanoconazole and luliconazole in the treatment of dermatophytosis. Terbinafine tended to have superior clinical efficacy compared to the azoles tested, although this difference was not statistically significant against luliconazole. This apparent superiority may be due to the fungicidal activity of terbinafine compared to the fungistatic effect of the other two drugs.

Topics: Administration, Topical; Animals; Antifungal Agents; Dermatomycoses; Disease Models, Animal; Guinea Pigs; Imidazoles; Male; Naphthalenes; Terbinafine; Treatment Outcome; Trichophyton

The in vitro activity of luliconazole (NND-502), a novel imidazole antifungal agent, against dermatophytes and several other groups of medically important fungi including the rare causative agents of dermatomycoses, was studied. The luliconazole susceptibility tests were performed with a total of 58 fungal strains of 23 species of fungi grouped into dermatophytes, dematiaceous fungi, hyaline hyphomycetes, yeastlike fungi, and zygomycetes using a broth microdilution method with RPMI 1640 medium. The minimum inhibitory concentration (MIC) values for luliconazole were compared with those of three reference drugs, lanoconazole (LCZ), bifonazole (BFZ), and terbinafine (TBF), all of which have been popular for the topical treatment of dermatophytosis, cutaneous candidiasis, and other superficial fungal infections in Japan. Luliconazole inhibited growth of all filamentous fungi except zygomycetes at low concentrations (MIC, < or =0.004-0.125 microg/ml), with dermatophytes being most susceptible (MIC, < or =0.004-0.008 microg/ml). The susceptibility of these filamentous fungi to luliconazole was almost equal to that to LCZ, and surpassed TBF and BFZ, although to a lesser extent; yeastlike fungi were also susceptible to luliconazole (MIC, 0.125-4 microg/ml). Again the anti-yeastlike fungi activity of luliconazole was at the same level as LCZ and was greater than that of BFZ and TBF. In contrast to BFZ and TBF, however, luliconazole and LCZ were virtually inactive against zygomycetes.

Topics: Antifungal Agents; Culture Media; Dermatomycoses; Fungi; Humans; Imidazoles; Microbial Sensitivity Tests

The in vitro activity of NND-502, a novel antifungal imidazole compound, was tested against the three major Malassezia species by an agar dilution method with modified Dixon medium and compared with the activities of three reference antifungal drugs of topical use, lanoconazole (LCZ), bifonazole (BFZ) and terbinafine (TBF). The geometric mean (GM)-MICs of NND-502 for 25 strains of M. furfur, 15 strains of M. sympodialis and ten strains of M. slooffiae were approximately 1.4, 0.1 and 1.0 mg/l, respectively, showing the greatest activity against M. sympodialis and the least against M. slooffiae. These values were similar to that of LCZ, but four to 69 times lower than that of BFZ and two to three times lower than that of TBF. The results suggest that NND-502 might be beneficial in the treatment of Malassezia-associated skin diseases.

Topics: Antifungal Agents; Dermatomycoses; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Heterocyclic Compounds; Humans; Imidazoles; In Vitro Techniques; Malassezia; Microbial Sensitivity Tests; Naphthalenes; Species Specificity; Terbinafine; Tinea Versicolor

In vitro and in vivo antidermatophyte activities of NND-502, a new imidazole antimycotic agent, were compared with those of two existing antifungal agents, lanoconazole and terbinafine. NND-502 exhibited strong in vitro antifungal activity against Trichophyton spp.; its MIC was 1 to 4 times lower than that of lanoconazole or terbinafine. In an in vivo study with a guinea pig model of tinea pedis, 7-day topical treatment with a 0.5% solution of NND-502 (dissolved in polyethylene glycol 400) was more effective than that with a 0.5% solution of either lanoconazole or terbinafine for eradicating fungi from the infected feet. When the duration of treatment was shortened to 3 days, a topical 1% solution of NND-502 achieved a complete mycological cure, while topical 1% solutions of lanoconazole and terbinafine did not.

Topics: Animals; Antifungal Agents; Arthrodermataceae; Dermatomycoses; Guinea Pigs; Imidazoles; Microbial Sensitivity Tests; Tinea Pedis