Challenges and new discoveries in the treatment of leishmaniasis.

Leishmaniasis is a parasitic disease caused by a hemoflagellate, Leishmania spp. The parasite is transmitted by the bite of an infected female phlebotomine sandfly. The disease is prevalent throughout the world and in at least 88 countries. Human leishmanial infections may manifest in any of the four most common forms. Depending on the causative species, it can manifest as cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), diffused cutaneous leishmaniasis (DCL), or visceral leishmaniasis (VL). Although there are nearly 25 compounds having antileishmanial effects, only a few are used for humans and most of these are parenteral. The oldest was urea stibamine, developed in India in 1922. The original drug had severe toxic effects, and later on its pentavalent compounds were prepared, which remained the sole treatment modality for several decades and saved millions of lives. However, reports of unresponsiveness to pentavalent sodium antimony gluconate (SAG) started in the 1970s, and in some parts of India about a quarter of kala-azar cases are reported to have developed resistance even to its higher doses. This development led to successful clinical trials of pentamidine and amphotericine B. The latter, an antifungal compound, was also found to be highly nephrotoxic, and to minimize these side effects various colloidal and lipid formulations have been prepared. These preparations are comparatively safe but are exorbitantly costly. In the past two decades, more focus has been given to finding oral drugs to minimize injection-associated complications, including blood-borne infection. Various drugs were reported effective, including antifungal ketoconazole. However, the most promising drug found is an anticancer compound, miltefosine, that belongs to the alkylphosphocholine group. The drug has undergone experimental and clinical trials and found to be 94%-97% effective. However, the drug cannot be given during pregnancy and shows severe gastrointestinal side effects. Moreover, its cost will be another limiting factor. Other drugs such as paromomycin, allopurinol, and sitamaquine have been reported with variable cure rates. Because of these limitations, a combination therapy, preferably coupled with specific parasite enzyme inhibitors, is the only hope.