Abstract

Ursolic acid (UA) is a triterpene with a broad array of pharmacological activities. In leishmaniasis, UA killed different species of parasites, and it was active in the experimental model of cutaneous and visceral leishmaniasis. Thus, the objective of this work was to study the therapeutic efficacy of the conventional drugs amphotericin B (AmB) or glucantime (Glu) combined with UA in experimental visceral and cutaneous leishmaniasis, respectively. L. (L.) infantum-infected hamsters were treated with AmB alone or combined with UA. L. (L.) amazonensis-infected BALB/c mice were treated with Glu alone or combined with UA. Animals were treated for 15 consecutive days by intraperitoneal or intralesional routes. Following one week after the last dose, the tissue parasitism and cellular immune responses were analyzed. Hamsters treated with 0.2 and 1.0 mg/kg of AmB plus 1.0 mg/kg of UA showed low hepatic and splenic parasitisms; however, AmB given as monotherapy did not reduce the number of viable parasites in the spleen of treated animals. In cutaneous leishmaniasis, Glu given as monotherapy was inactive at 2.0 mg/kg, showed mild activity at 10.0 mg/kg, and at 50.0 mg/kg was highly active at eliminating parasites in the skin. When animals were treated with Glu plus UA, higher leishmanicidal activity was observed in comparison to all groups treated with monotherapy schemes, and such activity was related to lesion improvement and upregulation of IFN-γ production. Altogether, data suggest that the association of drugs for the treatment of leishmaniasis can increase the efficiency of the treatment and decrease the toxicity associated to the conventional drugs.

Highlights

  • Leishmaniasis is a parasitic disease that is found mainly in tropical and subtropical areas, and has a prevalence of approximately 12 million cases; over 350 million people live in areas at risk of transmission [1]

  • In order to avoid the emergence of parasites resistance, increase the efficacy, and decrease the total amount of classical drugs used in the therapy, the aim of this study is to investigate if the association between ursolic acid (UA) with amphotericin B or glucantime can improve the efficacy of the treatment for leishmaniasis

  • Clinical studies have indicated that combined treatments can have three major consequences: (1) the clinical effects may be the sum of the effect of each drug alone; (2) the effect of adding a second drug may exceed the individual effect of each drug alone, or (3) the interaction between two drugs have opposite desired actions [10]

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Summary

Introduction

Leishmaniasis is a parasitic disease that is found mainly in tropical and subtropical areas, and has a prevalence of approximately 12 million cases; over 350 million people live in areas at risk of transmission [1]. Considering the main clinical forms, approximately 58,000 cases of visceral and 220,000 cases of cutaneous leishmaniases are officially reported per year [2]. Depending on the infecting species, several clinical forms of leishmaniasis can be characterized, such as visceral or cutaneous forms. Visceral leishmaniasis (VL) or kala-azar is a severe and potentially. Cutaneous leishmaniasis (CL), on the other hand, can manifest as a single skin lesion at the vector bite site to less common clinical forms with multiple nodules throughout the body, such as anergic cutaneous diffuse leishmaniasis that can cause deformities and sequelae [3]

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