Biology Reference
In-Depth Information
1.1.3 Leishmania Species
The human leishmaniases are caused by at least 21
Leishmania
species. The
parasite is transmitted to humans by the bite of female sandflies (Lutzomyia ssp
and Phlebotomus ssp) and, depending on the infecting species, may cause cutane-
ous (CL), mucocutaneous (MCL), or visceral (VL) leishmaniasis. CL manifests
as localized lesions on exposed regions of the skin, which may or may not be self-
healing. MCL is a complication of CL that results in extensive destruction of the
mucous membranes of the nose, mouth, or throat. Although not lethal, CL and, in
particular, MCL can be severely disfiguring and the cause of social stigmatization.
VL affects the internal organs, including the liver, spleen, lymph nodes, and bone
marrow. Symptoms include fever, enlarged liver and spleen, anemia, anorexia, and
weight loss and are fatal if not treated. The leishmaniases occur in five continents,
are endemic in 88 countries, and affect 12 million people worldwide (Stuart et al.
2008
). CL occurs predominantly in the Middle East, MCL in Central and South
America, and VL mostly in Bangladesh, Brazil, India, Nepal, and Sudan. VL kills
approximately 51,000 people every year and its occurrence is increasing in South-
western Europe, where it has emerged as an opportunistic infection of the immu-
nocompromised, particularly those with HIV (Alvar et al.
2008
). The increased
incidence of the disease in this region has been linked to transmission caused by
infected drug users sharing needles.
1.2 Therapies Currently in Clinical Use or in Development
Despite the fact that approximately 500 million people worldwide are at risk from
kinetoplastid-related diseases, advances in the development of new, safer, and more
efficacious therapies have lagged far behind those of drugs for more profitable
indications. According to the Drugs for Neglected Diseases initiative, of the 1,556
new drugs approved between 1975 and 2004, only 6 (0.4%) were developed for the
most neglected diseases (i.e., HAT, Chagas disease, and leishmaniasis) (Chirac and
Torreele
2006
). Being predominantly afflictions of the world's poorest populations,
there is little or no financial incentive for development of new drugs. Consequently,
many treatments in use today consist of drugs that were introduced over 50 years
ago. These drugs are far from ideal, with major problems including toxicity,
resistance, difficult administration regimens, and prohibitively high cost (Stuart
et al.
2008
).
The mainstay treatment for early-stage HAT consists of two drugs, suramin and
pentamidine, used to treat the East and West African forms of the disease, respec-
tively. Neither drug can cross the blood-brain barrier and consequently they are
not effective against late-stage disease. Two drugs, melarsoprol and eflornithine,
are currently used for late-stage disease. Melarsoprol, an arsenic-containing com-
pound, is highly toxic and causes death in 1 in 20 patients due to encephalopathy.
Eflornithine is only effective for the West African disease and its use is predominantly
