Biomedical Engineering Reference
In-Depth Information
Once injected into the skin, the parasites invade the local phagocytic host cells,
including neutrophils. Promastigotes, which are the infective form are acid sensitive
and inhibit phagosome-endosome fusion through unique lipophosphoglycan mole-
cules on their surface (Descoteaux and Turco
1999
; Miao et al.
1995
). Promastigotes
transform into amastigotes and after that, the inhibition is lifted. Amastigotes, that
are metabolically most active at acidic environment, depend on the harsh environ-
ment of the phagolysosome of resident macrophages where they survive and multi-
ply (Joshi et al.
1993
). Dissemination then occurs locally and distant macrophages
are infected. In visceral leishmaniasis liver, spleen and bone marrow macrophages are
colonized, in cutaneous and mucocutaneous leishmaniasis skin macrophages and
dendritic cells including Langerhans cells are colonized.
The amastigotes living inside the macrophage's phagolysosomes located in dif-
ferent anatomical areas present major structural and phenomenological barriers that
antileishmanial drugs have to overcome.
7.1
Conventional Treatments
Pentavalent antimonials (Sb
v
) (meglumine antimoniate and sodium stibogluconate)
were introduced in 1945 and remain effective treatment for some forms leishmania-
sis, but the requirement for up to 28 days of parenteral administration, the variable
efficacy against visceral and cutaneous leishmaniasis and the emergence of signifi-
cant resistance are all factors limiting the drug's usefulness.
Diamidine pentamidine is used as a second-line drug when Sb
v
have proved inef-
fective although it is highly toxic. Amphotericin B (AmB) (Fungizone, colloidal
dispersion of amphotericin and deoxycholate), is highly effective for the treatment
of Sb
v
resistant
L. donovani
visceral leishmaniasis and cases of muco-cutaneous
leishmaniasis that have not responded to Sb
v
, but it highly toxic and needs slow
parenteral infusion over 4 h. The development of lipid-associated amphotericine
formulations has reduced toxicity an extended plasma half-life in comparison to the
parent drug. Liposomal AmB (AmBisome) has proved to be effective and has been
approved by the Food and Drug Administration, but high cost have limited its use
(Croft and Coombs
2003
).
7.2
Preclinical Delivery Systems
7.2.1
Visceral Leishmaniasis
From the middle ยด1970s, a series of articles addressed the use of antileishmanial
drugs loaded in liposomes for selective delivery to the liver and spleen mac-
rophages infected with visceral leishmaniasis. Early applications started with
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