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Drug development

Chemotherapy remains the most important element in the control of VL as there are currently no vaccines to prevent VL infection. All current treatments suffer from significant drawbacks, i.e. parenteral route of administration, length of treatment (21 to 28 days), toxicity, or/and cost which limits their utilisation in disease endemic areas. In addition, the drugs currently in clinical development are either reformulations of earlier medicines, combination therapies or the result of therapeutic switching and therefore do not offer new alternatives to patients suffering from Leishmaniasis. The current anti-Leishmanial drugs and their limitations are:

Pentavalent antimonials (Sb) remain the primary first-line treatment in most parts of the world. It is a long (20-40 days depending on geographic area) and toxic treatment (3-5% death due to treatment). In addition, parasite resistance to pentavalent antimonial drugs is confirmed in Bihar State, India and could develop in other regions of the Indian sub-continent and in Africa.

Amphotericin B, now the second line drug against antimonyn (Sb) resistant cases in India, requires careful administration and shows nephrotoxicity. AmBisome™, an amphotericin B liposomal formulation, has remarkable activity even in a single dose in India, but its cost is prohibitive (€ 240 for WHO - € 2,500 for the brand) and it requires slow intra-venous infusion.

Two new therapeutic agents, miltefosine and paromomycin, have recently been developed and have raised hopes for improved treatment. Miltefosine was introduced in India in 2002 and has completed Phase IV trials. It has been registered for cutaneous Leishmaniasis (CL) in Colombia and is on trial against other forms of CL. A low cost parenteral formulation of paromomycin (aminosidine), completed Phase III clinical trials and was registered for VL in India in 2006; it is currently in Phase III clinical trials in East Africa. A topical paromomycin formulation has completed Phase II clinical trials for CL in Tunisia. However, both agents have been shown to rapidly select for resistance in laboratory studies. They may have only a short clinical usage unless strategies to minimise resistance are put in place with, for example, a use only in specific treatment centers or in combinations. The extensive use of miltefosine is also limited by teratogenicity and the requirement for women of childbearing age to take contraceptives for up to 2 months after completion of treatment.

There is only one other drug in clinical trials for the treatment of VL, namely the 8-aminoquinoline sitamaquine. Sitamaquine, a potential oral drug, completed Phase IIb trials in India in 2007.

In conclusion, despite some progress for VL in treatment options in India (but not East Africa), no ideal drugs are available that fulfill the major requirements for efficient anti-Leishmanial therapy, including high efficacy, low toxicity, easy administration, low costs, and avoiding occurence of drug resistant parasites. Novel concepts towards identification and optimization of drug leads, such as the ones described in this proposal, are urgently needed to overcome the current situation and more efficiently combat and eventually eradicate this deadly disease.