Antifungal drugs combinations: a patent review 2000-2015

ABSTRACT

Introduction: Combination therapy has emerged as an approach to improve the efficacy of antifungal drugs. Its main objective is to achieve synergistic interaction with higher antifungal properties and lower toxic effects than each substance alone.

Areas covered: Twenty-four patents disclosed in the period of 2000-2015 were covered in this review. Twenty of them were devoted to pharmacodynamic potentiation, while four were dedicated to pharmacokinetic actions.

Expert opinion: The common characteristic of most patents published in this area is that the main partner is a commercial antifungal drug. In the most innovative combinations the second component was either a modifier of proton homeostasis, an antibody, an inhibitor of the adhesion of epithelial or endothelial cells or a keratinolytic agent that improves the skin penetration. The evaluation of synergism is always made with simple in vitro methods, which constitutes a weakness of the disclosed patents, due to the lack of in vivo studies, since the in vitro tests cannot predict the in vivo behavior. Also, it is surprising that none of the patents analyze the toxicity of the new combinations, taking into account that one of the main objectives of the combinations is to reduce the toxicity of the existing antifungal drugs.

KEYWORDS:

• Antifungal
• combination
• synergism
• mycoses

Article highlights

• Combination antifungal therapy has emerged as an alternative to monotherapy for patients that fail to respond to standard antifungal treatments.

• Antifungal synergy is achieved with two compounds acting on different fungal targets or with one compound increasing the penetration of an antifungal agent, thus helping to reach the site of action.

• We review here 24 patents disclosed from 2000 to 2015 comprising new antifungal combinations to treat human fungal infections. The common characteristics of the published patents were as follows: (a) at least one partner was a commercial antifungal drug, and (b) the evaluation of synergism was always made with simple methods (mainly disk diffusion and checkerboard).

• The soil fungus metabolite (+)-FKI-0076 22 (a 2-derivative of methyl 3,5-dimethoxybenzoate) appears as a promising partner for combination with azole antifungal drugs.

• The most innovative patented combinations dealing with the pharmacodynamic enhancement of antifungal effects comprise either a modifier of proton homeostasis or an antibody as the partner of the antifungal drug.

• Patents dealing with pharmacokinetic interactions contain either an inhibitor of the adhesion of epithelial or endothelial cells or a keratinolytic agent as the partner of the antifungal drug.

This box summarizes key points contained in the article.

Financial and competing interests disclosure

The authors were supported by the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) under grant numbers PICT 2013-645 and PiCT 2014-1170; the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) under grant number PIP 112-201201-00444; and the Universidad Nacional de Rosario under grant number 1BIO381. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.