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      Spotlight on tavaborole for the treatment of onychomycosis

      review-article
      ,
      Drug Design, Development and Therapy
      Dove Medical Press
      tavaborole, boron-based antifungals, oxaboroles, onychomycosis

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          Abstract

          Onychomycosis is a fungal nail plate infection that has been increasing in prevalence. A variety of oral and topical anti-fungal agents are currently available but their use is limited by their adverse effect profile, drug–drug interactions, and limited efficacy. Therefore, there is a great need for newer anti-fungal agents. Tavaborole is one of these newer agents and was approved by the US Food and Drug Administration in July 2014 for the topical treatment of mild to moderate toenail onychomycosis. Tavaborole is a novel, boron-based anti-fungal agent with greater nail plate penetration than its predecessors, due to its smaller molecular weight. It has proven through several Phase II and III trials that it can be a safe and effective topical agent for the treatment of mild to moderate toenail onychomycosis without the need for debridement. In this paper, we review the landscape of topical and systemic treatment of onychomycosis, with particular attention to the pharmacokinetics, safety, and efficacy of topical tavaborole.

          Most cited references44

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          An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site.

          Aminoacyl-transfer RNA (tRNA) synthetases, which catalyze the attachment of the correct amino acid to its corresponding tRNA during translation of the genetic code, are proven antimicrobial drug targets. We show that the broad-spectrum antifungal 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), in development for the treatment of onychomycosis, inhibits yeast cytoplasmic leucyl-tRNA synthetase by formation of a stable tRNA(Leu)-AN2690 adduct in the editing site of the enzyme. Adduct formation is mediated through the boron atom of AN2690 and the 2'- and 3'-oxygen atoms of tRNA's3'-terminal adenosine. The trapping of enzyme-bound tRNA(Leu) in the editing site prevents catalytic turnover, thus inhibiting synthesis of leucyl-tRNA(Leu) and consequentially blocking protein synthesis. This result establishes the editing site as a bona fide target for aminoacyl-tRNA synthetase inhibitors.
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            A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns.

            Onychomycosis, a fungal infection of the nail bed, is responsible for up to 50% of nail disorders. Although several surveys have been conducted in different parts of the world, there have been no multicenter epidemiologic surveys of onychomycosis in North America. A 12-center study was undertaken to (1) determine the frequency of onychomycosis, (2) identify organisms recovered from the nails, and (3) determine the antifungal susceptibility of isolates. A total of 1832 subjects participated in this study and completed a comprehensive questionnaire, and nail clippings were collected for potassium hydroxide examination and culturing. The frequency of onychomycosis, as defined by the presence of septate hyphae on direct microscopy and/or the recovery of a dermatophyte, was found to be 13.8%. In general, the dermatophyte isolates were susceptible to the antifungals tested. Because of the limited number of large-scale studies, the baseline incidence is not firmly established. However, the higher frequency of onychomycosis in this study may confirm the suspected increase in incidence of disease in North America.
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              Fungicidal drugs induce a common oxidative-damage cellular death pathway.

              Amphotericin, miconazole, and ciclopirox are antifungal agents from three different drug classes that can effectively kill planktonic yeast, yet their complete fungicidal mechanisms are not fully understood. Here, we employ a systems biology approach to identify a common oxidative-damage cellular death pathway triggered by these representative fungicides in Candida albicans and Saccharomyces cerevisiae. This mechanism utilizes a signaling cascade involving the GTPases Ras1 and Ras2 and protein kinase A, and it culminates in death through the production of toxic reactive oxygen species in a tricarboxylic-acid-cycle- and respiratory-chain-dependent manner. We also show that the metabolome of C. albicans is altered by antifungal drug treatment, exhibiting a shift from fermentation to respiration, a jump in the AMP/ATP ratio, and elevated production of sugars; this coincides with elevated mitochondrial activity. Lastly, we demonstrate that DNA damage plays a critical role in antifungal-induced cellular death and that blocking DNA-repair mechanisms potentiates fungicidal activity.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                20 November 2015
                : 9
                : 6185-6190
                Affiliations
                Department of Dermatology, University of Connecticut School of Medicine, Farmington, CT, USA
                Author notes
                Correspondence: Justin Finch, Department of Dermatology, University of Connecticut School of Medicine, 21 South Road, Farmington, CT 06032, USA, Tel +1 860 679 4600, Fax +1 860 679 4759, Email finch@ 123456uchc.edu
                Article
                dddt-9-6185
                10.2147/DDDT.S81944
                4662369
                0cbe400c-6c6b-42f6-9812-6494c8dfce7e
                © 2015 Jinna and Finch. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                tavaborole,boron-based antifungals,oxaboroles,onychomycosis

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