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Abstract
The oral administration of dapsone (DAP) for the treatment of cutaneous leishmaniasis (CL) is effective, although serious hematological side effects limit its use. In this study, we evaluated this drug for the topical treatment of CL. As efficacy depends on potency and skin penetration, we first determined its antileishmanial activity (IC50 = 100 μM) and selectivity index in vitro against Leishmania major-infected macrophages. In order to evaluate the skin penetration ex vivo, we compared an O/W cream containing DAP that had been micronized with a pluronic lecithin emulgel, in which the drug was solubilized with diethylene glycol monoethyl ether. For both formulations we obtained similar low flux values that increased when the stratum corneum and the epidermis were removed. In vivo efficacy studies performed on L. major-infected BALB/c mice revealed that treatment not only failed to cure the lesions but made their evolution and appearance worse. High plasma drug levels were detected and were concomitant with anemia and iron accumulation in the spleen. This side effect was correlated with a reduction of parasite burden in this organ. Our results evidenced that DAP in these formulations does not have an adequate safety index for use in the topical therapy of CL.
Highlights
Leishmaniasis is a set of infectious diseases caused by intracellular protozoan parasites of the genus Leishmania
We evaluated the cytotoxicity of DAP in these cells, as they are the most frequently found type of skin cells and are involved in skin repair and wound healing
The number of L. major and L. braziliensis amastigotes decreased at increasing doses (Figure 1)
Summary
Leishmaniasis is a set of infectious diseases caused by intracellular protozoan parasites of the genus Leishmania. Therapy for CL is based on the use of pentavalent antimonials, pentamidine, miltefosine, and amphotericin B (AmB) They have variable efficacy, serious side effects, high cost, and prolonged treatment that affects patient adherence. Parasite strains resistant to some of these treatments have led to failure of therapy in many cases As these chemical approaches do not guarantee successful treatment of CL, the World Health Organization (WHO) recommends finding more effective oral or topical treatments with relatively less adverse effects [2]. In this context, topical treatments are desirable because of the lower systemic toxicity and costs, the ease of use and accessibility, and the higher patient compliance. Apart from the differences in efficacy depending on the Leishmania species, PM and its combinations caused erythema, skin irritation, and pain [5]
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