Evaluation of the Efficacy of ME1111 in the Topical Treatment of Dermatophytosis in a Guinea Pig Model

Abstract

The treatment of dermatophytoses, including onychomycosis, has come a long way over the past few decades with the introduction of oral antifungals (e.g., terbinafine and itraconazole). However, with these advancements in oral therapies come several undesirable effects, such as kidney and liver toxicity, along with drug-drug interactions. Consequently, there is a need for new topical agents that are effective against dermatophytosis. ME1111 is a topical antifungal under development. In this study, the in vivo efficacy of ME1111 was compared to that of ciclopirox in the topical treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea pig model. Animals were treated with the topical antifungals starting at 3 days postinfection, with each agent being applied once daily for seven consecutive days. After the treatment period, the clinical and mycological efficacies were evaluated. The data showed that both antifungals demonstrated significant clinical and mycological efficacies; however, ME1111 showed clinical efficacy superior to that of ciclopirox (46.9% and 25.0%, respectively, with a P value of <0.001). The potent efficacy of ME1111 could be attributed to its properties, such as low keratin binding. Dermatophytoses, such as onychomycosis, are infections of the hair, nail, and skin caused principally by the Trichophyton, Epidermophyton, and Microsporum fungal genera. Two of the most common of these etiological agents of skin mycoses are Trichophyton rubrum and Trichophyton mentagrophytes. Though fungal skin infections caused by these organisms may not be life threatening, they are extremely persistent and result in considerable discomfort, affecting patients' quality of life. Current oral therapies (e.g., terbinafine and itraconazole) are associated with a number of adverse events and drug-drug interactions, making them less desirable. Aside from oral therapies, most topical therapies have been proven to be inadequate, due to their inability to penetrate the tough layers of the nail plate. Even with these advances, however, complete cure is often unattainable, as up to 15 to 20% of patients experience relapses (1). Therefore, the development of safer and more effective antifungal agents is needed.2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5-methylphenol (ME1111) is a member of a new class of compounds that has shown strong fungicidal properties in nonclinical studies and is a novel selective inhibitor of succinate dehydrogenase of Trichophyton species (2). ME1111 is a novel antidermatophytic drug discovered by Meiji Seika Pharma Co., Ltd. (Tokyo, Japan) through an optimization process directed at selecting compounds with (i) potent antidermatophyte activity, (ii) favorable physicochemical and nail permeation properties, and (iii) a small molecular size. Further research demonstrated that ME1111 is a first-in-class, lowmolecular-weight compound with antifungal activity, mediated by the inhibition of succinate dehydrogenase (complex II), a critical enzyme involved in mitochondrial respiratory electron ...

Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy

“…It is highly active in vitro and in vivo against Trichophyton rubrum and Trichophyton mentagrophytes and shows excellent human nail permeability (1)(2)(3)(4). A previous study on its mechanism of action revealed that the molecular target of ME1111 was succinate dehydrogenase (complex II) in the mitochondrial electron transport system (5).…”

Preparation, and Assessment of Antidermatophyte Activity of Miconazole–Urea Water-Soluble Film

“…where T is the total number of positive hair roots in the test group and K is the total number of positive hair roots in the infected untreated group. Total score indicates the mean clinical scores of animals in the same group (Garvey et al, 2015;Long et al, 2016).…”

“…In addition, they have large body surface, giving a sufficient area to do tests and hence determine the clinical as well as the mycological efficacies. Garvey et al (2015) and Long et al (2016) used a guinea pig model to assess the efficacies of various antifungals for the treatment of dermatophytosis. Accordingly, the aim of this work is to evaluate the combined effect of miconazole as an antifungal agent as well as urea as a penetration enhancer against T. rubrum in vitro and in vivo.…”