Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 786

receptor on macrophages. It was proposed that the small size (8-20 nm) of these
nanodisks was responsible for their recognisement by macrophages.
In the search for less invasive vias of administration, oral administration of
meglumine antimoniate-b-cyclodextrin complexes led to smaller skin lesions on
experimental cutaneous leishmaniasis (Demicheli et al. 2004 ; Frézard et al. 2008 ).
Equally less invasive are the topical treatments, but to date no satisfactory results
have been achieved by this route. A few attempts were accomplished in order to
improve drug absorption. The use of permeation enhancers like ethanol signifi-
cantly reduced the lesion size on experimental cutaneous leishmaniasis ( L. major )
upon topically applied dispersion of Amphocil and Abelcet (amphotericin interca-
lated with sheets of phospholipid) in solution containing 5-25% ethanol, over ani-
mals treated with dispersed Fungizone (Frankenburg et al. 1998 ). On the other
hand, topical AmB (Amphocil in 5% ethanol) has been successful in treatment of
L. major infected patients in Israel (Vardy et al. 2001 ; Zvulunov et al. 2003 ).
A 15% ointment of the highly hydrophilic antibiotic paromomycin, associated
to the permeation enhancer methylbenzethonium chloride (12%) (marketed in
Israel as Leshcutan), is relatively effective for treatment ( L major, L. tropica,
L. mexicana and L. panamensis ) (El-On et al. 1986, 1992 ), but local side-effects are
observed frequently due to the permeation enhancer (Arana et al. 2001 ; Armijos
et al. 2004 ; Minodier and Parola 2007 ). A second formulation combined paromo-
mycin with urea and while non-irritating its efficacy remains largely undistin-
guished, with reported cure rates little better than placebo in Iran (47% vs. 44%)
and Tunisia (27% vs. 18%) (Asilian et al. 1995 ; Ben Salah et al. 1995 ; Iraji and
Sadeghinia 2005 ). New cream formulation (WR279,396) containing paromomycin
and gentamicin, showed high cure rates (94% vs. 71% placebo) in treating patiens
with L. major cutaneous leishmaniasis with only mild local irritation (Ben Salah
et al. 2009 ).
Recently, the effect of topical liposomes containing paromomycin sulfate was
evaluated in L. major infected mice (Jaafari et al. 2009 ). Mice that received
~500 nm liposomes (SoyPc: chol: propylenglicol: vitamin E, 15: 27: 0.3 wt.%),
twice a day for 4 weeks showed a significantly smaller lesion size in the mice in the
treated groups than in the mice in the control group. Eight weeks after the begin-
ning of the treatment, the mice treated with liposomes were completely cured. The
spleen parasite burden was significantly lower in mice treated with liposomes than
in mice treated with PBS or control liposomes. Using a simmilar approach
(Carneiro et al. 2010 ) showed that 500-300 nm fluid liposomes containing paromo-
mycin enhanced in vitro drug permeation across stripped skin and improved the
in vivo antileishmanial activity in L. major infected mice.
Topical administration was also addressed by our research group, by determin-
ing the in vitro leishmanicidal activity of sunlight triggered photodynamic ultrade-
formable liposomes (Montanari et al. 2010 ). A hydrophobic Zn phthalocyanine
with 20% anti-promastigote activity and 20% anti-amastigote activity against
L. braziliensis after 15 min sunlight irradiation (15 J/cm 2 ), hadd 100% and 80%
anti-promastigote and anti-amastigote activity respectively, at the same light dose
when loaded in ultradeformable liposomes. In the absence of host cells toxicity,