Abstract
BackgroundChemotherapy is still a critical issue in the management of leishmaniasis. Until recently, pentavalent antimonials, amphotericin B or pentamidine compounded the classical arsenal of treatment. All these drugs are toxic and have to be administered by the parenteral route. Tamoxifen has been used as an antiestrogen in the treatment and prevention of breast cancer for many years. Its safety and pharmacological profiles are well established in humans. We have shown that tamoxifen is active as an antileishmanial compound in vitro, and in this paper we analyzed the efficacy of tamoxifen for the treatment of mice infected with Leishmania amazonensis, an etiological agent of localized cutaneous leishmaniasis and the main cause of diffuse cutaneous leishmaniasis in South America.Methodology/Principal FindingsBALB/c mice were infected with L. amazonensis promastigotes. Five weeks post-infection, treatment with 15 daily intraperitoneal injections of 20 mg/kg tamoxifen was administered. Lesion and ulcer sizes were recorded and parasite burden quantified by limiting dilution. A significant decrease in lesion size and ulcer development was noted in mice treated with tamoxifen as compared to control untreated animals. Parasite burden in the inoculation site at the end of treatment was reduced from 108.5±0.7 in control untreated animals to 105.0±0.0 in tamoxifen-treated mice. Parasite load was also reduced in the draining lymph nodes. The reduction in parasite number was sustained: 6 weeks after the end of treatment, 1015.5±0.5 parasites were quantified from untreated animals, as opposed to 105.1±0.1 parasites detected in treated mice.Conclusions/SignificanceTreatment of BALB/c mice infected with L. amazonensis for 15 days with tamoxifen resulted in significant decrease in lesion size and parasite burden. BALB/c mice infected with L. amazonensis represents a model of extreme susceptibility, and the striking and sustained reduction in the number of parasites in treated animals supports the proposal of further testing of this drug in other models of leishmaniasis.
Highlights
Protozoan parasites of Leishmania genus are the etiological agents of leishmaniasis, a disease distributed worldwide with a broad spectrum of clinical manifestations according to the causative species and immunological status of the host
Miltefosine has been approved in India for the therapy of visceral leishmaniasis [3], but its efficacy on the treatment of American cutaneous leishmaniasis has been shown to be variable depending on the causative species [4],[5],[6],[7]
In the present study we demonstrate that L. amazonensis-infected BALB/c mice treated with tamoxifen for 2 weeks presented a significant reduction in lesion size and parasite burden
Summary
Protozoan parasites of Leishmania genus are the etiological agents of leishmaniasis, a disease distributed worldwide with a broad spectrum of clinical manifestations according to the causative species and immunological status of the host. In South America, Leishmania amazonensis is one of the causative agents of localized cutaneous leishmaniasis and the most important agent of diffuse cutaneous leishmaniasis (DCL), a devastating disease with uncontrolled progression, characterized by multiple skin lesions and vaste numbers of amastigotes. Pentavalent antimonials, amphotericin B or pentamidine compounded the classical arsenal of treatment. All these drugs are toxic and have to be administered by the parenteral route. We have shown that tamoxifen is active as an antileishmanial compound in vitro, and in this paper we analyzed the efficacy of tamoxifen for the treatment of mice infected with Leishmania amazonensis, an etiological agent of localized cutaneous leishmaniasis and the main cause of diffuse cutaneous leishmaniasis in South America
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