Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

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Drug Resistance in Leishmaniasis

Leishmaniasis– current chemotherapy and recent advances in the search for novel drugs

The clinical manifestations of leishmaniasis depend on com­ plex interactions between the virulence characteristics of the infecting Leishmania species and the immune responses of its host. The result is a spectrum of disease ranging from localized skin lesions to diffuse involvement of the reticuloendothelial system. Human disease has traditionally been divided into three major clinical syndromes: visceral, cutaneous, and mucosal leishmaniasis; however, a number of variants exist. Further­ more, a single Leishmania species can produce more than one clinical syndrome, and each syndrome is caused by multiple species. The true incidence and prevalence of leishmaniasis is uncer­ tain because many cases go undiagnosed or unreported in areas where the infection is endemic. In 1993, the World Health Organization estimated that 350 million people worldwide were at risk for infection. The incidence of cutaneous leishmaniasis has been estimated to be 1.0-1.5 million cases per year, and

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Clinical Spectrum of Leishmaniasis

Chemotherapy of trypanosomiases and leishmaniasis

Although three new drugs or drug formulations, liposomal amphotericin B (AmBisome), miltefosine and paromomycin should be available for the treatment of visceral leishmaniasis (VL) within the next year, they all suffer from limitations of either cost, specific toxicities or parenteral administration. As part of research to identify better treatments for VL and cutaneous leishmaniasis (CL), alternative and potentially cheaper formulations of amphotericin B, alklyphosphocholines other than miltefosine and improved formulations of paromomycin for CL have been identified. Other drugs or compounds that have demonstrated activity in experimental rodent models of infection include licochalcone derivatives, quinoline derivatives, bisphosphonates and a maesabalide; further chemistry based upon these leads is warranted. The process for discovery and development of new antileishmanials would also benefit from improved models, for example, transfected parasites, and non invasive methods of measuring parasite load in rodent models of infection.

Current scenario of drug development for leishmaniasis.

Background: A controlled study of the efficacy of topical paromomycin sulfate (PR) and methylbenzethonium chloride (MBCI) in cutaneous leishmaniasis (CL) has not yet been performed. Objective: The therapeutic effect of an ointment containing 15% PR and either 12% or 5% MBCI (15/12 or 15/5 P-ointment) on patients suffering from Old World CL was examined in a randomized, double-blind, cross-over study. Methods: Thirty-nine patients with Old World CL caused by Leishmania major were treated topically, twice daily, for 10 to 20 days with 15/12 or 15/5 P-ointment and 10 to 20 days with a placebo ointment to achieve a total of 30 days of treatment in all groups. Results: In the P-ointment-treated groups, 74.2% (29 of 39 patients) of the patients were cured versus 26.6% (4 of 15 patients) in the placebo-treated group. Little difference was found between the 15/12 and 15/5 P-ointment groups. Conclusion: In most of the patients treated with the active ingredients, total elimination of the parasites was achieved within the first 10 days of treatment.

Marcello H. Grunwald

Papers

Topical treatment of Old World cutaneous leishmaniasis caused by Leishmania major: A double-blind control study