**1. Introduction**

[119] Shakya N., Sane SA., Vishwakarma P., Gupta S. Enhancement in therapeutic efficacy of miltefosine in combination with synthetic bacterial lipopeptide, Pam3Cys against experimental Visceral Leishmaniasis. Experimental Parasitology 2012; 131(3) 377-82.

376 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

Leishmaniasis is an infection caused by a parasite from *Leishmania* genus, which can manifest itself through different forms: cutaneous (with skin ulcers) [1, 2], visceral (hepato and spleno‐ megaly) [3], and diffuse integumentary form (injuries beyond the superficial skin barrier, hitting cartilages and deeper connective tissues) [4]. Leishmaniasis vectors are diptera from *Psychodida* family, which includes hematophagous from *Phlebotomus* genus (Old World) and *Lutzomuyia* genus (New World), with wide distribution in warm and temperate climates [5] (Figure 1).

In the New World, eight Leishmania species are responsible for men diseases: Leishmania braziliensis, Leishmania guyanensis, Leishmania panamensis, Leishmania lainsoni, Leishma‐ nia mexicana, Leishmania amazonensis, Leishmania venezuelensis and Leishmania chagasi [7]. Thus, leishmaniasis can be found in four continents, being considered endemic in 88 countries, of which 72 are in development [5].

Different protozoa species are able to live inside sand flies (insect vectors) from *Phlebotomi‐ nae* subfamily and vertebrate hosts. This parasite lives between two different types of hosts due to its significant morphological changes. In vertebrate hosts, *Leishmania* is at amastigote form without flagella and inside the digestive tract of the sand flies, the parasite is flagellated and fusiform, and receives the name of promastigote, as shown in Figure 2.

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**Figure 1.** Distribution in Old World and New World of cutaneous (left, marked in orange) and visceral (right, marked in purple) leishmaniasis. Affected areas marked according to the World Health Organization [6].

**Figure 2.** *Leishmania sp* (A) promastigote and (B) amastigote (right) forms.

In Figure 3, two important cellular structures used to identify the *Leishmania* parasites are highlited in the first image - the nucleus, indicated by the letter N and the kinetoplast, indicated by the letter K. These structures are kept in the distinct methacyclogenesis stages. After completing the cycle modifications, *Leishmania* becomes able to infect mammalian cells.

Different forms of leishmaniasis are transmitted through the bite of female sand flies. The transmission cycle begins when, during a bite, the mosquito ingests mammalian blood infected with amastigote forms. Once installed in the digestive tract of the host, *Leishmania* passes through the process of differentiation, methacyclogenesis, and the new form of the parasite, promastigote, can be inject in mammalian blood again during a bite, thus completing the disease transmission cycle (Figure 4).

Nanoparticle Technology: An alternative approach for Leishmaniasis Treatment http://dx.doi.org/10.5772/57283 379

**Figure 3.** Different transition stages between (a) promastigote and (f) amastigote forms of *Leishmania braziliensis*.

**Figure 4.** Life cycle of the parasite.

**Figure 1.** Distribution in Old World and New World of cutaneous (left, marked in orange) and visceral (right, marked

In Figure 3, two important cellular structures used to identify the *Leishmania* parasites are highlited in the first image - the nucleus, indicated by the letter N and the kinetoplast, indicated by the letter K. These structures are kept in the distinct methacyclogenesis stages. After completing the cycle modifications, *Leishmania* becomes able to infect mammalian cells.

Different forms of leishmaniasis are transmitted through the bite of female sand flies. The transmission cycle begins when, during a bite, the mosquito ingests mammalian blood infected with amastigote forms. Once installed in the digestive tract of the host, *Leishmania* passes through the process of differentiation, methacyclogenesis, and the new form of the parasite, promastigote, can be inject in mammalian blood again during a bite, thus completing the

in purple) leishmaniasis. Affected areas marked according to the World Health Organization [6].

378 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

**Figure 2.** *Leishmania sp* (A) promastigote and (B) amastigote (right) forms.

disease transmission cycle (Figure 4).

## **2. Current treatments**

In 1912, Vianna [9] observed that the tartar emetic (an antimony compound) was effective in the treatment of American Integumentary Leishmaniasis. Due to toxicity and serious collateral damages associated to the tartar emetic use, i.e. gastrointestinal intolerance and cardiotoxic effects, the trivalent antimonials (Table 1) were replaced by quinquivalent compounds (Table 2). In 1936, Schmidt introduced in medical therapy antimony (V) sodium gluconate, commer‐ cially known as Solustibosan® (Bayer) or Pentostam® (Glaxo Wellcome) [10, 11].

**Table 1.** Chemical structure of trivalent antimonials used in medical clinic, with their respective chemical and commercial names [5].

One of the most commonly used drugs is N-methylglucamine antimoniate, which are espe‐ cially effective in the treatment of cutaneous and visceral leishmaniasis. This drug provokes fast regression of the clinical and hematological manifestations of the disease, as well as the dead of the parasite [5]. However, due to its low dosages and discontinuous treatments, some therapy failures, an increase of the resistant forms of the parasites started to show up [12-14].

The World Health Organization preconizes that antimonials dosages Should not trespass 20 mg/kg/day, and due to its elevated toxicity, the dosage of antimony ingested per day should not be higher than 850 mg [12]. However, the N-methylglucamine antimoniate is rapidly absorbed and about 90% of the antimony ingested is excreted through the kidneys in the firsts 48 hours [15]. Consequently, there is a necessity to administrate high doses of the drug, in continuous regimen, so an elevated dosage of antimony is assured in the tissues, and therefore the treatment efficacy is obtained.


**Table 2.** Chemical structure of quinquivalent antimonials used in medical clinic [5].

**2. Current treatments**

380 Leishmaniasis - Trends in Epidemiology, Diagnosis and Treatment

commercial names [5].

the treatment efficacy is obtained.

In 1912, Vianna [9] observed that the tartar emetic (an antimony compound) was effective in the treatment of American Integumentary Leishmaniasis. Due to toxicity and serious collateral damages associated to the tartar emetic use, i.e. gastrointestinal intolerance and cardiotoxic effects, the trivalent antimonials (Table 1) were replaced by quinquivalent compounds (Table 2). In 1936, Schmidt introduced in medical therapy antimony (V) sodium gluconate, commer‐

Antimony (III) potassium tartrate [11]/

Stibophen, Repodral, Fuadina

Antimony (III) sodium thioglicolate [11]

Sodium antimony (III) bis (catechol – 3,5 – disulfonate)

Tartar emetic

[11]/

**Table 1.** Chemical structure of trivalent antimonials used in medical clinic, with their respective chemical and

One of the most commonly used drugs is N-methylglucamine antimoniate, which are espe‐ cially effective in the treatment of cutaneous and visceral leishmaniasis. This drug provokes fast regression of the clinical and hematological manifestations of the disease, as well as the dead of the parasite [5]. However, due to its low dosages and discontinuous treatments, some therapy failures, an increase of the resistant forms of the parasites started to show up [12-14].

The World Health Organization preconizes that antimonials dosages Should not trespass 20 mg/kg/day, and due to its elevated toxicity, the dosage of antimony ingested per day should not be higher than 850 mg [12]. However, the N-methylglucamine antimoniate is rapidly absorbed and about 90% of the antimony ingested is excreted through the kidneys in the firsts 48 hours [15]. Consequently, there is a necessity to administrate high doses of the drug, in continuous regimen, so an elevated dosage of antimony is assured in the tissues, and therefore

cially known as Solustibosan® (Bayer) or Pentostam® (Glaxo Wellcome) [10, 11].

**Structural form Chemical/commercial names**

High doses of N-methylglucamine antimoniate generate a various diversity of collateral effects, such as nephritis, gastrointestinal, cardiovascular and respiratory disturbances. In some cases, besides destroying the parasites, some patients are led to death [11]. The antimony can still be detected in the hair of the patients a year after the treatment is finished [16]. The toxicity of antimony can be explained by the fact that there are some evidences describing that a metabolic conversion happens inside the macrophages transforming antimony V (Sb5+) in antimony III (Sb3+) [13] and the antimony III is proved to be more lethal to the *Leishmania* species [5]. So the hypothesis is that the antimony V works as prodrug, and the conversion to antimony III is what guarantee its efficacy after administration [17], and the antimony III interferes in the β-oxidation process of fat acids of the parasites, as so in the glycolysis, taking the ATP to a low level inside the cell [12]. This way, the antimony III would be responsible for the toxicity of the drug as well as its therapeutic activity [18].

Besides antimonials, other medicines have been used in the treatment of the various forms of leishmaniasis, among them can be found pentamidine, amphotericin B, paromomycin, and miltefosine (Table 3) [5]. Pentamidine is also effective in the trypanosomiasis treatment [19] and this drug is also highly toxic, showing as collateral effects hypoglycemia, hypotension, cardiologic changes, nephrotoxicity and even death [12]. Amphotericin B is an antibiotic produced by *Streptomyces* nodosus and can produce nephrotoxicity, depleting the potassium and magnesium levels of the organism [20]. Paromomycin is an aminoglycoside antibiotic active against *Leishmania* species in in vitro and in vivo forms. It is been highly tested in India, where antimonial standard treatments are not effective [5]. Miltefosine is an alkyl phospholi‐ pidic anticancer drug and it is in intensive tests also in India. It is showing excellent results and may be the first oral treatment against visceral leishmaniasis [21].

**Table 3.** Other chemicals used in leishmaniasis therapy, with their respective chemical and commercial names.

### **3. Alternative treatments**

Association of some drugs used in leishmaniasis treatment within lipid vesicles called liposomes is one of the alternatives used to reduce the undesirable effects. This association increases the efficiency and the concentrations of these drugs in the tissues, reducing drasti‐ cally their toxicity [22, 23]. The mechanism that could explain the effectiveness of liposomes is that they inhibit oxygen consumption by the parasite membrane [24].

One practical exemple of this association happens with Amphotericin B, a compound used for the treatment of calazar patients that are resistant to pentamidine. Amphotericin B can be toxic because they can associate with human cell cholesterol as they do to the ergosterol in the parasite plasmatic membrane [6]. To reduce this inappropriate recognition, there are some commercial formulations that associate the Amphotericin B to lipids (Ambisome, Abelcet, Amphotec). Besides their effectiveness in reducing this drug toxicity, they are very expensive and their use becomes basically impractical in poor countries [25].

However, there are some studies searching some low-cost methods of producing these drugs. One example is a formulation with a similar lipid composition to Abelcet, but with some different variables, such as conformation and molecular weight, that may influence the drug release and action in the organism [26]. This formulation was found to be much more effective and less toxic than Abelcet and, although it is less efficient than Ambisome, it is also less expensive for use in leishmaniasis treatment.
