Intracellular Bacteria and Protozoa - Intracellular Delivery: Fundamentals and Applications - page 788

of parasite attachment, where the lysosomes fuse with the plasma membrane and
contribute to the formation of the PV (Rodriguez et al. 1996 ; Schenkman et al.
1988 ). Desialylation of the PV by T. cruzi trans-sialidase then facilitates the lysis
of the membrane by a parasite-secreted pore forming toxin (Tc-TOX), which is
most active at acidic pH and leads to liberation of the parasite into the cytosol
(Andrew 1994 ).
Because of the short and asymptomatic acute phase, the cytoplasmatic amastig-
otes presents the major structural and phenomenological barriers that antichagasic
drugs have to overcome.

8.1 Conventional Treatments

Two drugs that were introduced for clinical use in the late 1960s and early 1970s
are commonly indicated for the treatment of Chagas disease: benznidazole
( N -benzyl-2-nitroimidazole acetamide) and nifurtimox (3-methyl-4-[(5-
nitrofurfurylidene) amino] thiomorpholine-1, 1-dioxide). Benznidazole at 5 mg/kg/
day 30-60 days acts via reductive stress and involves covalent modification of
macromolecules by nitroreduction intermediates Nifurtimox at 8-10 mg/kg/day
90 days acts via the reduction of the nitro group to unstable nitroanion radicals,
which react to produce highly toxic, reduced oxygen metabolites (superoxide
anion, hydrogen peroxide). T. cruzi is deficient in detoxification mechanisms for
oxygen metabolites and is more sensitive to oxidative stress than vertebrate cells
(Rodrigues Coura and de Castro 2002 ). Theses drugs have significant activity in the
acute (up to 80% of parasitological cures in treated patients, defined as a negative
result for all parasitological and serological tests) and early chronic phases (up to
60% cures) (de Andrade et al. 1996 ; Sosa Estani et al. 1998 ; 1999 ).
The main disadvantages of these drugs are: (i) low effectiveness in the chronic
phase of the disease (<20%), that is the most frequent clinical presentation
(Cançado 1999 ); (ii) regional variations in efficacy due to naturally resistant T.cruzi
strains (Murta et al. 1998 ); (iii) high rate of patient noncompliance due to drug side
effects; (iv) long period of treatment (30-60 days), and dose-dependent toxicity;
(v) need for monitoring under specialized medical supervision; (vi) nifurtimox has
been only intermittently produced since 1997 by Bayer while benznidazole, Roche
has transferred rights and technology to Brazilian government in 2007, making
Pharmaceutical Laboratory of Pernambuco the drug sole manufacture in world
(with help of DNDi).

8.2 Preclinical Delivery Systems

Recently we have extensively reviewed the state-of-the-art in the development of
nanotechnological strategies against Chagas disease (Romero and Morilla 2010 ).