**2. Current drugs**

nodes. With the progression of VL, splenomegaly and hepatomegaly lead to a distended abdomen and pain. Eventually, VL may lead to death caused by secondary infections, severe anemia, or organ failure [4]. Both TL and VL are endemic diseases in several countries. In fact, the number of cases of leishmaniasis may be underestimated because only 40 of the 88 countries

**Scheme 1.** Leishmaniasis life cycle. 1- sand flies inject promastigotes during blood meals ;2-promastigote infects mac‐ rophages and other types of mononuclear phagocytic cells;3-promastigotes transform into amastigotes; 4-amasti‐ gotes multiply. 5- sand flies become infected by ingesting macrophages infected with amastigotes during blood meals; 6- parasitized cells ; 7- in sand flies, amastigotes transform into promastigotes, in the gut; 8- promastigotes di‐

The World Health Organization (WHO) estimates that 1.6 million new leishmaniasis cases occur annually, of which 500,000 correspond to VL (90% of them occurring in Bangladesh, Brazil, Ethiopia, India, Nepal, and Sudan) and 1.1 million to CL (90% of them occurring in Afghanistan, Algeria, Brazil, Iran, Peru, Saudi Arabia, Sudan, and Syria) [7]. Leishmaniasis currently affects an estimated 12 million people and approximately 350 million people live at risk of infection [1], whereas an estimated half a million people die annually of VL. In addition,

where the disease frequently occurs report cases on a regular basis [5, 6].

vide and migrate to proboscis based on CDC, 2013 [1].

352 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

Currently, most antileishmanial drugs can be considered orphan drugs. In fact, leishmania‐ sis, Chagas disease, are examples of tropical neglected diseases (TND) as they receive little attention from governments and the pharmaceutical industry. For instance, by the 2000s, global investment in new anti-parasitic drugs was only about 0.1% of global investment in research [11, 12]. Additionally, the lack of human vaccines for leishmaniasis makes chemotherapy the primary method used to control the disease. Despite the existence of several chemotherapics to treat human leishmaniasis, many of them are new formula‐ tions of ancient drugs [13]. The chemotherapeutic agents currently used in the treatment of VL and TL such as stibogluconate of sodium (Pentostam®), *N*-methylglucantime (Glucantime®), pentamidine (Pentacarinato®), and amphotericin B (Fungizone®) do not possess activity when orally administered and require parenteral administration for long periods [14]. In addition, those chemotherapeutic agents are very expensive and cause severe side effects due to their high toxicity [15].

Taken together, all these factors contribute to poor patient adherence or abandonment of treatment. In turn, treatment failure has a great impact on the spread of the disease and the emergence of drug-resistant strains. However, the introduction of new chemotherapeu‐ tic agents, including liposomal amphotericin B (AmBisome®), paramomycin, and miltefo‐ sin has certainly improved the current scenario for the treatment of leishmaniasis. AmBisome® has become the first-choice drug for treating VL in several countries. For instance, this treatment is currently used in Bihar, India, because pentavalent antimonials have become less effective against parasites [16, 17]. However, none of these drugs are free of severe side effects and the development of new strategies and/or alternative therapeu‐ tic agents remain crucial.

The incorporation of amphotericin B into lipid formulations has brought new perspec‐ tives to the treatment of leishmaniasis, resulting in the incorporation of several other drugs to different lipid formulations, including meglumine antimoniate [18], furazolidone [19], paromomycin sulfate [20] and miltefosin [21]. Conventional chemotherapeutics usually have difficulty reaching target tissues in therapeutic concentrations and are also associated with toxic effects on healthy organs and tissues. Thus, drug delivery approaches should improve the efficacy, specificity, tolerability, and therapeutic index of antiparasitic agents [12]. However, despite advances in the efficacy of existing drugs, the toxic potential of these substances must be considered. Thus, the search for new strategies and/or alternative therapeutic agents is crucial.
