Abstract
The production of ergosterol lipid involves the activity of different enzymes and is a crucial event for the Leishmania membrane homeostasis. Such enzymes can be blocked by azoles and allylamines drugs, such as the antifungal butenafine chloride. This drug was active on parasites that cause cutaneous and visceral leishmaniasis. Based on the leishmanicidal activity of butenafine chloride and considering the absence of reports about the therapeutic potential of this drug in cutaneous leishmaniasis, the present work is aimed at analyzing the efficacy of butenafine formulated in two different topical delivery systems, the self-nanoemulsifying drug delivery systems (BUT-SNEDDS) and in a SNEDDS-based nanogel (BUT-SNEDDS gel) as well as in the free form in experimental cutaneous leishmaniasis. Physical studies showed that both formulations were below 300 nm with low polydispersity (<0.5) and good colloidal stability (around -25 mV). Increased steady-state flux was reported for nanoenabled butenafine formulations with reduced lag time in Franz cell diffusion assays across Strat-M membranes. No toxic or inflammatory reactions were detected in animals treated with BUT-SNEDDS, BUT-SNEDDS gel, or butenafine. Animals topically treated with butenafine (free or nanoformulated) showed small dermal lesions and low tissue parasitism. Furthermore, BUT-SNEDD gel and butenafine presented similar efficacy than the standard drug Glucantime given by the intralesional route. Increased levels of IFN-γ were observed in animals treated with BUT-SNEDDS gel or butenafine. Based on these data, the antifungal drug butenafine chloride can be considered an interesting repurposed drug for the treatment of cutaneous leishmaniasis.
Highlights
Leishmaniasis is an infectious disease caused by protozoans from the Trypanosomatidae family, Kinetoplastida order, and Leishmania genus, that affect humans, wild and domestic animals, and invertebrates belonging to the Lutzomyia and Phlebotomus genuses [1, 2]
Amphotericin B is effective in treating leishmaniasis [8], but it interacts with the host cell membrane inducing mild to severe adverse effects in patients, including fever and renal and gastrointestinal toxicities [9, 10]
L. (L.) amazonensis-infected BALB/c mice were divided into seven groups: group 1 (G1) was constituted by infected animals that received only vehicle solution (PBS plus 1% DMSO); groups 2 (G2) and 3 (G3) were treated with blank self-nanoemulsifying drug delivery systems (SNEDDS) or blank SNEDDS gels, respectively; group 4 (G4) was treated with BUT-SNEDDS; group 5 (G5) was treated topically with BUTSNEDDS gel, group 6 (G6) was treated topically with butenafine (10 mg of butenafine) solubilized in PBS plus 1% of DMSO, and group 7 (G7) was injected intralesionally with 100 mg/kg of Glucantime
Summary
Leishmaniasis is an infectious disease caused by protozoans from the Trypanosomatidae family, Kinetoplastida order, and Leishmania genus, that affect humans, wild and domestic animals, and invertebrates belonging to the Lutzomyia and Phlebotomus genuses [1, 2]. The cutaneous form of leishmaniasis is caused by different Leishmania species; a spectrum of clinical signs can be found, ranging from a single localized skin. The treatment of all clinical forms of leishmaniasis is based on few therapeutic alternatives, such as pentavalent antimonials and amphotericin B [4]. In some geographic areas, such as in India, drug-resistant parasites have been frequently detected [7]. In such situations, amphotericin B is used as the secondline drug. An amphotericin B cream (3% w/w, Anfoleish) is currently under clinical trials, but preliminary results have shown variable efficacy in patients with CL as a result of limited skin permeability [14], while a range of adverse effects such as itching, redness, peeling dryness, and irritation of the skin were observed in patients [15]. The prevalence of the disease with distinct outcomes, the ineffectiveness, and toxicity of the available drugs emphasizes the need for more active and less toxic treatments based on natural or synthetic molecules [19,20,21]
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