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      In Vitro additive effect on griseofulvin and terbinafine combinations against multidrug-resistant dermatophytes

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          Abstract

          ABSTRACT Griseofulvin (GF) and terbinafine (TF) are commonly used drugs to treat dermatophytosis, a fungal infection of the skin. Today there is an increase in drug resistance to these antifungals which highlight the need for alternative synergistic therapies. Minimum Inhibitory Concentration (MIC) of GF and TF were determined against fungi clinical isolates from local hospitals with values ranging 0.03-2.0 µg mL-1 and 0.24-4.0 µg mL-1, respectively. A checkboard test was used to determine the combination of GF:TF which could induce an additive effect against the fungi isolates Multidrug-resistant isolates showed susceptibility after treatment with 16:2 µg mL-1 GF:TF. An MTT assay further verified that GF and TF combinations have greater additive effect against pathological and multidrug-resistant isolates than antifungals alone. Herein we disclose GF:TF combinations that could constitute as a possible new anti-dermatophyte therapy.

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          Most cited references27

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          Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

          The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of efflux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the preliminary testing of new antifungal agents. In general, many years are required from discovery of a new antifungal to clinical use. However, the development of new antifungal strategies will reduce the therapeutic time and/or increase the quality of life of patients.
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            The biology and chemistry of antifungal agents: a review.

            In recent years their has been an increased use of antifungal agents and has resulted in the development of resistance to drugs. Currently, use of standard antifungal therapies can be limited because of toxicity, low efficacy rates. Different types of mechanisms contribute to the development of resistance to antifungals. This has given raise to search for a new heterocycle with distinct action or multitargeted combination therapy. This review addresses the areas such as the underlying mechanisms, eight different targets such as ergosterol synthesis, chitin synthesis, ergosterol disruptors, glucan synthesis, squalene epoxidase, nucleic acid synthesis, protein synthesis, microtubules synthesis. The clinically employed drugs along with the current research work going on worldwide on different heterocycles are discussed. In recent advances various heterocycles including imidazole, benzimidazole etc., twenty three scaffolds and their lead identification are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Comparison of Etest, chequerboard dilution and time-kill studies for the detection of synergy or antagonism between antifungal agents tested against Candida species.

              Currently, there is considerable debate regarding the best in vitro method for testing antifungal combinations against Candida spp. In this study, we compared the results obtained by chequerboard dilution, time-kill studies and Etest for several antifungal combinations against Candida spp. Three Candida albicans isolates (fluconazole MICs of 1.0, 32 and >256 mg/L) and three non-albicans Candida isolates (C. glabrata, C. tropicalis and C. krusei) were tested in RPMI 1640 medium. By chequerboard testing, the majority of antifungal combinations were found to be indifferent. Notably, antagonism was identified by time-kill studies and by Etest for combinations of amphotericin B-fluconazole, but it was not detected by the chequerboard method. Pre-exposure of isolates to fluconazole did not affect results of the Etest or chequerboard method, but it did increase the frequency of antagonism noted by time-kill methods. This study indicates that chequerboard dilution testing in RPMI medium may not reliably detect the attenuation of amphotericin B activity. Of the three methods, Etest was the simplest to use and yielded reproducible results for testing antifungal combinations.
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                Author and article information

                Journal
                bjps
                Brazilian Journal of Pharmaceutical Sciences
                Braz. J. Pharm. Sci.
                Universidade de São Paulo, Faculdade de Ciências Farmacêuticas (São Paulo, SP, Brazil )
                2175-9790
                2018
                : 54
                : 2
                : e17149
                Affiliations
                [1] Porto Alegre Rio Grande do Sul orgnameUniversidade Federal do Rio Grande do Sul orgdiv1Faculdade de Farmácia Brazil
                [2] Porto Alegre Rio Grande do Sul orgnameUniversidade Federal do Rio Grande do Sul orgdiv1Departamento de Química Orgânica Brazil
                Article
                S1984-82502018000200623 S1984-8250(18)05400200623
                10.1590/s2175-97902018000217149
                30ae35de-1211-42ed-b0c3-621ccbbd26cc

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 19 April 2017
                : 07 November 2017
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 27, Pages: 0
                Product

                SciELO Brazil

                Categories
                Article

                Multidrug-resistant fungi,Dermatophyte,Griseofulvin,Drug combination.,Terbinafine

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