To evaluate the combination effects of anti-onychomycosis drugs, the minimum inhibitory concentrations of topical (efinaconazole, luliconazole, and tavaborole) and oral (itraconazole and terbinafine) drugs for Trichophyton rubrum and Trichophyton interdigitale (8 each, with a total of 16 strains) were determined using the microdilution checkerboard technique based on the Clinical and Laboratory Standard Institute guidelines. No antagonism was observed between the topical and oral drugs against all the tested strains. Efinaconazole with terbinafine exerted a synergistic effect on 43.8% of the strains tested (7/16 strains) and efinaconazole with itraconazole on 12.5% (2/16 strains). Conversely, luliconazole showed no synergistic effect with terbinafine but was synergistically effective with itraconazole against 31.3% of the strains (5/16 strains). Tavaborole showed no synergistic effect with terbinafine and was synergistically effective with itraconazole against 18.8% of the strains (3/16 strains). The results suggest that a combination of topical and oral drugs could be a potential clinical option for onychomycosis treatment, and overall, the efinaconazole and oral drug combination would be the most advantageous among the tested combinations.
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.
Use of oral antifungals in the treatment of onychomycosis is commonplace; but their use can be limited by safety and patient concerns. Due to their broader safety margins, topical antifungals (efinaconazole, tavaborole, and ciclopirox) are a useful option in the treatment of mild-to-moderate onychomycosis in the USA, but their antifungal activity has yet to be directly compared. This study aims to identify important factors contributing to in vivo efficacies of the three topical antifungals. Minimum inhibitory concentrations (MICs) were determined by Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth microdilution. The MIC90 values of efinaconazole, tavaborole, and ciclopirox for T. rubrum were 0.0078, 8.0, and 0.50 μg/mL, respectively. The MIC90 values for T. mentagrophytes were 0.016, 8.0, and 0.50 μg/mL, respectively. Efinaconazole showed potent fungicidal activity in keratin-containing medium, whereas tavaborole was fungistatic, and ciclopirox not active. In the guinea pig model of onychomycosis, the therapeutic efficacy of efinaconazole was superior to those of tavaborole and ciclopirox. This study suggests that not only fungistatic activity (MIC), but also fungicidal activity in the presence of keratin, is an important factor contributing to the in vivo efficacy of topical antifungal drugs against onychomycosis.
Resveratrol (Rsv) has been shown to extend the lifespan of diverse range of species to activate sirtuin (SIRT) family proteins, which belong to the class III NAD + dependent histone de-acetylases (HDACs).The protein deacetylating enzyme SIRT1 has been implicated in the regulation of cellular senescence and aging processes in mammalian cells.However, higher concentrations of this natural compound cause cell death.Therefore, novel compounds that have reduced cellular toxicity will be required for anti-aging therapy, especially for dermatological treatments.In this study, the Luciferase (Luc) expression vector pGL4-SIRT1 containing 396-bp of the 5'-upstream region of the human SIRT1 gene was transfected into HeLa S3 cells and Luc assay was performed.The results showed that treatments with the natural compound, α-, β-and γ-thujaplicins increase the SIRT1 promoter activity more than that with Rsv.Moreover, we carried out multiple transfection of Luc reporter vectors containing 5'-upstream regions of various human telomere maintenance factor encoding genes, and observed that β-thujaplicin (hinokitiol) activates TERT, RTEL, TRF1, DKC1, RAP1 (TERF2IP) and TPP1(ACD) promoters.These results suggest that that the β-thujaplicin could be used as anti-aging drugs to delay cellular senescence through activating SIRT1 transcription along with strengthening stability of telomeres.
