Trends in Parasitology
Volume 19, Issue 11, November 2003, Pages 502-508
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Leishmaniasis– current chemotherapy and recent advances in the search for novel drugs

https://doi.org/10.1016/j.pt.2003.09.008Get rights and content

Abstract

The chemotherapy currently available for leishmaniasis is far from satisfactory. Resistance to the pentavalent antimonials, which have been the recommended drugs for the treatment of both visceral (VL) and cutaneous leishmaniasis (CL) for >50 years, is now widespread in India. Although new drugs have become available in recent years for the treatment of VL, including AmBisome®, the excellent but highly expensive liposomal formulation of amphotericin B, and the oral drug miltefosine, which has now been registered in India, treatment problems remain. Parenteral and topical formulations of the aminoglycoside paromomycin offer potential treatments for VL and CL, respectively. The search for new drugs continues, with bisphosphonates, for example, risedronate and pamidronate, and plant derivatives such as licochalcone A and quinoline alkaloids being reported to have activity against experimental animal infections. The immunomodulator imiquimod has proved to be an adjunct for CL therapy. Many potential drug targets have been identified in biochemical and molecular studies, and some have been validated. Attempts to exploit these targets are in progress.

Section snippets

Current recommendations

The drugs currently recommended for the treatment of leishmaniasis [7] include the pentavalent antimonials sodium stibogluconate [Pentostam™, GlaxoSmithKline (GSK); http://www.gsk.com] and meglumine antimoniate (Glucantime, Aventis, http://www.aventis.com), amphotericin B (Bristol-Myers Squibb; http://www.bms.com/) and its lipid formulation AmBisome® (Gilead; http://www.gilead.com/), and pentamidine (Aventis) (Table 2 and Figure 2). The antimonials were first introduced in 1945 and remain

Immunomodulation

Cure of leishmaniasis, probably even during chemotherapy, appears to be dependent upon the development of an effective immune response that activates macrophages to produce toxic nitrogen and oxygen metabolites to kill the intracellular amastigotes 6, 33, 34. This process is suppressed by the infection itself which downregulates the requisite signalling between macrophage and T cells, for example, the production of interleukin (IL)-12 or the presentation of major histocompatibility complex

Rational approach: possibilities and problems

New antileishmanial drugs are required and the favoured approach adopted by many to achieve this goal is to identify potential drug targets (either through biochemical studies or, increasingly, by mining the L. major genome database), validating them either chemically or genetically [40], and then identifying inhibitors that can serve as lead compounds to enter a drug development process. Much of this approach is similar to that being applied with many other pathogens (see Cowman and Crabb;

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