DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

this infection (Bern et al., 2007; Croft, 2008; Tarleton
et al., 2007). Both agents suppress parasitemia and can
cure the acute phase of Chagas’ disease in 60-80% of
cases; however, both drugs are toxic and must be taken
for long periods. A long-term clinical trial with results
expected in 2011 (BENEFIT) is currently underway to
provide clarification of the role of treatment in modulating
disease progression and preventing death
(http://clinicaltrials.gov/show/NCT00123916; Marin-
Neto et al., 2008). Field isolates vary with respect to
their susceptibility to nifurtimox and benznidazole.
Moreover, cross-resistance to both compounds can be
induced in the laboratory (Wilkinson et al., 2008).
Clearly, new drugs with better potency against parasites in
the chronic phase and with reduced toxicities are needed. A key factor
in new drug development for Chagas’ disease is the need for better
methods to assess parasitological cure. Several important reports
documenting significant advances in this area have recently been
published (Bustamante et al., 2008; Cooley et al., 2008).
Additionally, some promising strides toward the development of new
agents have been made. Inhibitors of an essential protease, cruzipain,
have anti-parasite activity, and one (K777) is in preclinical
development for the treatment of Chagas’ disease (Doyle et al., 2007).
In the absence of new drugs, however, alternative measures such as
improved vector control and housing accommodations have been
used to reduce the transmission of Chagas’ disease substantially in
Brazil, Chile, and Venezuela (World Health Organization, 1999).
Leishmaniasis. Leishmaniasis is a complex vector-borne
zoonosis caused by ~20 different species of obligate
intramacrophage protozoa of the genus Leishmania
(Chappuis et al., 2007; Croft 2008; Stuart et al., 2008).
Small mammals and canines generally serve as reservoirs
for these pathogens, which can be transmitted to humans
by the bites of some 30 different species of female phlebotomine
sandflies.
Various forms of leishmaniasis affect people in southern
Europe and many tropical and subtropical regions throughout the
world. Flagellated extracellular free promastigotes, regurgitated by
feeding flies, enter the host, where they attach to and become phagocytized
by tissue macrophages. These transform into amastigotes,
which reside and multiply within phagolysosomes until the cell
bursts. Released amastigotes then propagate the infection by invading
more macrophages. Amastigotes taken up by feeding sandflies
transform back into promastigotes, thereby completing the transformation
cycle. The particular localized or systemic disease syndrome
caused by Leishmania depends on the species or subspecies of
infecting parasite, the distribution of infected macrophages, and
especially the host’s immune response. In increasing order of systemic
involvement and potential clinical severity, major syndromes
of human leishmaniasis have been classified into cutaneous, mucocutaneous,
diffuse cutaneous, and visceral (kala azar) forms.
Leishmaniasis increasingly is becoming recognized as an AIDSassociated
opportunistic infection.
The classification, clinical features, course, and chemotherapy
of human leishmaniasis syndromes as well as the biochemistry
and immunology of the parasite and host germane to
chemotherapy have been recently reviewed (Chappuis et al., 2007;
Croft and Coombs, 2003; Stuart et al., 2008). Cutaneous forms of
leishmaniasis generally are self-limiting, with cures occurring
in 3-18 months after infection. However, this form of the disease
can leave disfiguring scars. The mucocutaneous, diffuse cutaneous,
and visceral forms of the disease do not resolve without
therapy. Visceral leishmaniasis caused by L. donovani is fatal
unless treated.
The list of current drugs useful for the treatment
of all forms of leishmaniasis has been described (Alvar
et al., 2006; Croft, 2008; Olliaro et al., 2005). The classic
therapy for all species of Leishmania is pentavalent
antimony (sodium antimony gluconate; sodium stibogluconate;
PENTOSTAM); resistance to this compound
has led to widespread failure of this drug in India,
although it remains useful in other parts of the world.
As an alternative, liposomal amphotericin B is a highly
effective agent for visceral leishmaniasis, and it is currently
the drug of choice for antimony-resistant disease
(Chappuis et al., 2007) (Chapter 57). Importantly, treatment
of leishmania has undergone major changes
owing to the success of the first orally active agent, miltefosine,
in clinical trials (Berman, 2008; Bhattacharya
et al., 2007). Miltefosine was approved in India for the
treatment of visceral leishmaniasis in 2002. The drug
also appears to have promise for the treatment of the
cutaneous disease and for the treatment of dogs, which
serve as an important animal reservoir of the disease
(Berman, 2008). Paromomycin has been used with success
as a parenteral agent for visceral disease (Sundar
et al., 2007), and topical formulations of paromomycin
have efficacy against cutaneous disease. Pentamidine
may also be used for cutaneous disease (Croft, 2008).
Other Protozoal Infections. Just a few of the many less
common protozoal infections of humans are highlighted
here.
Babesiosis, caused by either Babesia microcoti or B. divergens,
is a tick-borne zoonosis that superficially resembles malaria
in that the parasites invade erythrocytes, producing a febrile illness,
hemolysis, and hemoglobinuria. This infection usually is mild and
self-limiting but can be severe or even fatal in asplenic or severely
immunocompromised individuals. Currently recommended therapy
is with a combination of clindamycin and quinine for severe disease,
and the combination of azithromycin and atovaquone for mild or
moderate infections.
Balantidiasis, caused by the ciliated protozoan Balantidium
coli, is an infection of the large intestine that may be confused with
amebiasis. Unlike amebiasis, however, this infection usually
responds to tetracycline therapy.
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CHAPTER 50
CHEMOTHERAPY OF PROTOZOAL INFECTIONS