ABSTRACT
BACKGROUND: Effective transungual delivery of topical antifungal agents in onychomycosis has been hampered by poor nail permeation. To be effective they must have antifungal efficacy, and effectively permeate through the dense keratinized nail plate to the site of infection in the nail bed and nail matrix. The therapeutic efficacy of efinaconazole topical solution, 10% has been established in two phase 3 clinical trials in distal lateral subungual onychomycosis. OBJECTIVE: To investigate the transungual delivery of efinaconazole in onychomycosis patients and its fungicidal activity in the toenail. METHODS: Concentrations of efinaconazole were determined as part of a multi-center, open label study in forty onychomycosis patients following repeated application of efinaconazole topical solution, 5% and 10% to the toenails over 28 days, with a 2-week follow-up. Fungicidal activity against T. rubrum in the ventral layer of human nails was determined using an in vitro human nail infection model (ChubTur®). RESULTS: Efinaconazole concentrations in the nail were four orders of magnitude higher than MIC values of efinaconazole against dermatophytes. Further, nail drug concentrations were not influenced by the presence of disease or nail thickness, and maintained at high antifungal levels post-treatment. Efinaconazole was effective in reducing fungal viability, suggesting that sufficient amounts of efinaconazole were being delivered into the ventral layer of the nail plate.
CONCLUSIONS: Effective transungual delivery of efinaconazole was demonstrated. The high efinaconazole concentrations in patient toenails and fungicidal activity in vitro potentially contribute to the clinical efficacy reported in phase 3 studies.
Subject(s)
Antifungal Agents/therapeutic use , Foot Dermatoses/drug therapy , Onychomycosis/drug therapy , Triazoles/therapeutic use , Administration, Topical , Adult , Aged , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacokinetics , Drug Delivery Systems , Female , Follow-Up Studies , Humans , In Vitro Techniques , Male , Microbial Sensitivity Tests , Middle Aged , Nails/metabolism , Nails/microbiology , Onychomycosis/microbiology , Permeability , Triazoles/administration & dosage , Triazoles/pharmacokinetics , Trichophyton/drug effectsABSTRACT
There is increasing evidence that cathepsin B (CB), a lysosomal cysteine protease, is one of the toxic molecules that are secreted by activated microglia. We herein provide evidence that CB released by activated microglia may play a role in the methylmercury (MeHg)-induced pathological changes observed in the cerebellum of the adult rat. Pathological changes tended to progress slowly after treatment with MeHg (5 mg/kg) for 12 consecutive days. At 5 days after the final treatment of MeHg, there was a mild pyknotic change of the granule cells, whereas a marked accumulation of activated microglia was observed in the granule cell layer of the lingual and central lobe. At 8 days after the final treatment, intense pyknotic changes of the granule cells and the accumulation of activated microglia were observed throughout the cerebellar vermis. CB first significantly increased at 3 days after the final treatment of MeHg as the mature form. CB mainly increased in activated microglia which accumulated in the granule cell layer. The coadministration of CA074, an irreversible CB inhibitor, with MeHg significantly reduced the severity of pyknotic changes of the granule cells. Furthermore, primary cultured microglia secreted the mature CB in the culture medium following cellular activation. These observations strongly suggest that CB secreted by activated microglia is thus closely associated with the MeHg-induced severe pyknotic changes of the cerebellar granule cells. The treatment of CA074 could be a potentially effective therapeutic intervention to prevent the pathological changes in the cerebellum caused by ingestion of MeHg-contaminated food.
