title: Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis.
abstract: Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation.
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan yuuji.tabata@meiji.com.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Takei-Masuda
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan.
authors.forename: Natsuki
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Takahata
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohyama
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kaneda
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Iida
authors.affiliation: Meiji Seika Pharma Co., Ltd., Pharmaceutical Research Center, Yokohama, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Maebashi
mesh_terms: D000287:Administration, Topical; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007564:Japan; D007633:Keratins / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009262:Nails / Q000187:drug effects* / Q000382:microbiology*; D014009:Onychomycosis / Q000188:drug therapy*; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014249:Trichophyton / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: C000611893:2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol; D000935:Antifungal Agents; D010636:Phenols; D011720:Pyrazoles; D007633:Keratins