**1. Introduction**

Leishmaniasias is a complex of diseases caused by intracellular protozoan parasites that belong to the genus *Leishmania* (class: Kinetoplastida; order: Trypanosomatidae), for which there are more than 20 different species, and is transmitted by the bite of female phlebotomine sand flies (order: Diptera; family: Psychodidae; subfamily: Phlebotominae). Various species of phlebot‐ omine sand flies of the genus *Phlebotomus* are responsible for transmission of leishmaniasis in the Old World, and of the genus *Lutzomyia* in the New World [1]. *Leishmania* parasite has a digenetic life-cycle alternating between a mammalian host and insect vectors, phlebotomine sand flies, which are small (1.5-2 mm body length) insects mainly found in tropical and subtropical regions. *Leishmania* lives extracellularly as flagellated promastigotes in the gut and salivary glands of the sand fly vector, and intracellularly as amastigotes in the vertebrate host macrophages. *Leishmania* promastigotes, transmitted to mammalian skin by the bite of a female phlebotomine sand fly, invade human macrophages as the main host for the parasites, where *Leishmania* transforms into amastigotes and replicate intracellularly. Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization (WHO). The disease burden of leishmaniasis is high, with about 350 million people in 98 countries consid‐ ered at risk. Among parasitic diseases, leishmaniasis accounts for the second highest burden of disease after malaria, with a loss of about 2.4 million disability-adjusted life years (DALYs) [2, 3]. There are an estimated 1.5-2 million new cases per year, with 1.5 million cases of selfhealing, but disfiguring, (muco-)cutaneous leishmaniasis, and 500,000 cases of life-threatening visceral leishmaniasis [2, 3]. However, more than 90% of the world's cases of visceral leish‐ maniasis are in India, Bangladesh, Nepal, Sudan, and Brazil. Some species tend to cause cutaneous leishmaniasis (e.g., *L. major* and *L.tropica*), whereas others lead to cause visceral leishmaniasis (e.g., *L. infantum* and *L. donovani*). Leishmaniases are usually classified based on the clinical manifestations, leading to three major clinical forms, namely:

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Cutaneous leishmaniasis can be further divided into: a) localized (crusted papules or ulcers occur several weeks to months after sand fly bite inoculation on exposed skin, and lesions usually heal spontaneously); b) diffuse cutaneous (producing widespread skin lesions which resemble leprosy, being particularly difficult to treat; and patients cannot mount a cellmediated immune response to the *Leishmania* parasite, developing multiple, widespread cutaneous papules and nodules); c) recidivans (appearing as a recurrence of lesions at the site of apparently healed disease years after the original infection; and occurring typically on the face as an enlarging papule, plaque, or coalescence of papules that heals with central scarring, leading to facial destruction in some cases); d) post-kala-azar dermal leishmaniasis (a compli‐ cation of visceral leishmaniasis in areas where *L. donovani* is endemic, and characterized by a hypopigmented macular, maculopapular, and nodular rash that usually appears 6 months to 1 or more years after apparent cure of visceral leishmaniasis).

Another way to categorize leishmaniasis is based on geographic occurrence. Thus, Old World leishmaniasis, caused by *Leishmania* species found in Africa, Asia, the Middle East, and the Mediterranean, mainly leads to cutaneous or visceral forms of disease; and New World leishmaniasis, caused by *Leishmania* species found in endemic regions extending from southern USA to northern Argentina, mainly in Central and South America, generates cutaneous, mucocutaneous, and visceral forms of disease. It is interesting to note that distinct forms of leishmaniasis follow different clinical courses of the disease depending on the geographical location. Thus, post-kala-azar dermal leishmaniasis heals spontaneously in the majority of cases in Africa, but rarely in patients in India. This form of leishmaniasis, endemic to India and Sudan, is considered to have an important role in maintaining and contributing to transmission of the disease particularly in interepidemic periods of visceral leishmaniasis, acting as a reservoir for parasites. Post-kala-azar dermal leishmaniasis reflects the immune response of the individual to the *Leishmania* organism, and lesions may be numerous and persist for decades. Most forms of the disease are transmissible from non-human animals to people (zoonotic transmission), but some can be spread between humans (anthroponotic transmis‐ sion).

The chemotherapy currently available for the treatment of leishmaniasis is far from satisfactory and shows a series of problems, including toxicity, adverse side-effects, high costs and development of drug resistance [2, 4]. Thus, search for new antilesihmanial drugs is urgently needed.

### **2. Miltefosine as a new antileishmanial drug**

**•** Cutaneous leishmaniasis. It is the most common form of the disease, leading to a skin sore at the bite site, which erupts weeks to months after the person affected is bitten by sand flies,

**•** Mucocutaneous leishmaniasis. It occurs predominantly in the New World, starting with skin ulcers which spread, causing tissue damage and destruction, and certain *Leishmania* species migrate to the upper respiratory tract where destruction of the oropharynx and nose

**•** Visceral leishmaniasis. It is classically known as kala-azar, and also referred to as black fever, and Dumdum fever. It is the most serious and devastating form of the disease, where the parasites localize to the reticuloendothelial system, rather than to the skin, and migrate to and affect internal organs (usually spleen, liver, and bone marrow), producing a potentially lethal widespread systemic disease that is fatal if untreated. Visceral leishmaniasis is characterized by irregular bouts of fever, weight loss, substantial swelling of the spleen and liver, fatigue and anemia. The systemic infection of the liver, spleen and bone marrow leads to hepatomegaly, splenomegaly, lymph node enlargement, thrombocytopenia, and anemia.

Cutaneous leishmaniasis can be further divided into: a) localized (crusted papules or ulcers occur several weeks to months after sand fly bite inoculation on exposed skin, and lesions usually heal spontaneously); b) diffuse cutaneous (producing widespread skin lesions which resemble leprosy, being particularly difficult to treat; and patients cannot mount a cellmediated immune response to the *Leishmania* parasite, developing multiple, widespread cutaneous papules and nodules); c) recidivans (appearing as a recurrence of lesions at the site of apparently healed disease years after the original infection; and occurring typically on the face as an enlarging papule, plaque, or coalescence of papules that heals with central scarring, leading to facial destruction in some cases); d) post-kala-azar dermal leishmaniasis (a compli‐ cation of visceral leishmaniasis in areas where *L. donovani* is endemic, and characterized by a hypopigmented macular, maculopapular, and nodular rash that usually appears 6 months to

Another way to categorize leishmaniasis is based on geographic occurrence. Thus, Old World leishmaniasis, caused by *Leishmania* species found in Africa, Asia, the Middle East, and the Mediterranean, mainly leads to cutaneous or visceral forms of disease; and New World leishmaniasis, caused by *Leishmania* species found in endemic regions extending from southern USA to northern Argentina, mainly in Central and South America, generates cutaneous, mucocutaneous, and visceral forms of disease. It is interesting to note that distinct forms of leishmaniasis follow different clinical courses of the disease depending on the geographical location. Thus, post-kala-azar dermal leishmaniasis heals spontaneously in the majority of cases in Africa, but rarely in patients in India. This form of leishmaniasis, endemic to India and Sudan, is considered to have an important role in maintaining and contributing to transmission of the disease particularly in interepidemic periods of visceral leishmaniasis, acting as a reservoir for parasites. Post-kala-azar dermal leishmaniasis reflects the immune response of the individual to the *Leishmania* organism, and lesions may be numerous and persist for decades. Most forms of the disease are transmissible from non-human animals to people

1 or more years after apparent cure of visceral leishmaniasis).

and then heals in a few months to a year, leaving an unpleasant-looking scar.

442 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

ensues, resulting in extensive midfacial destruction and, occasionally, in death.

The control of leishmaniasis in the absence of vaccine depends solely on the choice of chemo‐ therapy. Additional complications in the treatment of leishmaniasis include intrinsic speciesspecific differences in drug susceptibility [5, 6] as well as differences in drug efficacy between geographical areas [7], which can reflect the genetic differences between *Leishmania* parasites at species and strain levels [8, 9]. The generation of drug resistance is a major concern in the treatment of leishmaniasis that can be worsened by the rather low number of drugs currently available in therapy, thus leading to the lack of a putative alternative for a drug to which resistance has arisen. In this regard, it is well known the increasing resistance against the widely used pentavalent antimonial compounds in India, where resistance rates have been shown to be higher than 60% in parts of the state of Bihar, in north-east India [10, 11]. Thus, search for novel anti-*Leishmania* drugs is desperately needed. In the last years a new drug has been included in the clinical arsenal of antileishmanial drugs named miltefosine (hexadecyl‐ phoshocholine) (Figure 1), which is orally administered and is effective against pentavalent antimonial compound-resistant *Leishmania* parasites. Following a number of successful clinical trials ranging from phase I/II to phase IV in the period 1996-2004, miltefosine was registered as a new antileishmanial drug in India in 2002 [12]. Miltefosine, registered under the trade name of Impavido®, is the first oral drug in leishmaniasis therapy, having being developed by Zentaris (Frankfurt, Germany) in close cooperation with WHO/Special Programme for Research & Training in Tropical Diseases (TDR), and currently being manufactured by Paladin (Quebec, Canada). The standard miltefosine treatment includes oral administration of 100-150 mg/day, depending on the body weight, for 28 days and is well tolerated, except for mild gastrointestinal side effects.

**Figure 1.** Chemical structures of edelfosine and miltefosine.

Miltefosine treatment leads to high cure rates in visceral leishmaniasis in India (*L. donovani*; 94% cure) [13]. However, different trials regarding the efficacy of miltefosine against cutaneous leishmaniasis in Colombia led to distinct outcomes ranging from a 90% cure [14] to an unsatisfactory cure rate of 69.8% [15]. Sensitivity to miltefosine is known to vary between *Leishmania* species [16]. In this regard, *L. braziliensis* seems to be somewhat refractory to miltefosine as shown in a number of clinical studies [14, 17-19]. Miltefosine efficacy against leishmaniasis lesions caused by *L. braziliensis*, which comprise more than 60% of cutaneous leishmaniasis in Colombia, fell to 49% [15], and was only 33% in Guatemala [14]. Additional clinical trials in Brazil showed a miltefosine cure rate of 75% and 71% for the treatment of cutaneous leishmaniasis caused by *L. braziliensis*[20] and *L. guyanensis*[21], respectively. Thus, these trials have challenged the therapeutical potential of miltefosine for the treatment of American cutaneous leishmaniasis. Miltefosine treatment has also led to approximately 70% cure rate for mucosal leishmaniasis due to *L. braziliensis* in Bolivia [18, 22], 53% for cutaneous leishmaniasis (33% for *L. braziliensis* infection, and 60% for *L. mexicana* infection) in Guatemala [14, 17, 23], and 63% for *L. tropica* infection in Afghanistan [23]. The above cure rates contrast with those reported for the treatment of visceral leishmaniasis (kala-azar) in India [12, 24] and Bangladesh [25] that were higher than 82%. These data highlight the great variability in the clinical outcome depending on the geographical area for reasons that are not well understood.

The main toxicity for miltefosine involves gastrointestinal organs in both animal and human studies. Thus, miltefosine frequently induces gastrointestinal side effects, such as anorexia, nausea, vomiting and diarrhea, that sometimes lead to drop out from treatment [2, 3, 24]. The testis and retina have been identified as target organs in rats, but the expected and corre‐ sponding effects and symptoms based on these observations have not been detected in clinical studies in humans [26]. Miltefosine distributes widely in body organs and is not metabolized by cytochrome P450 enzymes *in vitro*. Miltefosine has been found to be embryotoxic and fetotoxic in rats and rabbits, and teratogenic in rats, but not in rabbits [26]. Thus, miltefosine is potentially teratogenic, being contraindicated for use during pregnancy, and adequate contraception is required during treatment and for up to 3 months afterwards in women of child-bearing age [2, 3, 26]. An additional concern is the rapid *in vitro* generation of resistance to miltefosine [27-30] that could limit its clinical use.

Miltefosine is a member of a family of structurally-related compounds collectively known as synthetic alkylphospholipids (APLs), that target cell membranes and show pleiotropic actions with multiple biomedical applications in addition to their antitumor effect, which have been widely studied [31-35]. The advent of miltefosine as a new antileishmanial drug introduces APLs as putative novel drugs for the treatment of leishmaniasis. In addition, because of the numerous studies reported on the antitumor action of these compounds, it could be envisaged that the insight acquired for their antitumor action might be of use in the treatment of leish‐ maniasis.
