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

1424 Isospora belli, a coccidian parasite, causes diarrhea in
AIDS patients and responds to treatment with trimethoprimsulfamethoxazole.
Cyclospora cayetanensis, another coccidian parasite,
causes self-limited diarrhea in normal hosts and can cause
prolonged diarrhea in individuals with AIDS. It is susceptible to
trimethoprim-sulfamethoxazole.
Microsporidia are spore-forming unicellular eukaryotic fungal
parasites that can cause a number of disease syndromes, including
diarrhea in immunocompromised individuals. Infections with
microsporidia of the Encephalitozoon genus, including E. hellum,
E. intestinalis, and E. cuniculi, have been treated successfully with
albendazole, a benzimidazole derivative and inhibitor of β-tubulin
polymerization (Gross, 2003) (Chapter 51). Immunocompromised
individuals with intestinal microsporidiosis due to E. bieneusi (which
does not respond as well to albendazole) have been treated successfully
with the antibiotic fumagillin (Molina et al., 2002).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
ANTI-PROTOZOAL DRUGS
The myriad agents used to treat nonmalarial protozoal
diseases are presented alphabetically.
Amphotericin B
The pharmacology, formulation, and toxicology of amphotericin B
are presented in Chapter 57. Only those features of the drug pertinent
to its use in leishmaniasis are described here.
Antiprotozoal Effects. In 1997, the FDA approved liposomal amphotericin
B (AMBISOME) for the treatment of visceral leishmaniasis.
Amphotericin B is a highly effective antileishmanial agent that cures
>90% of the cases of visceral leishmaniasis in clinical studies, and it
has become the drug of choice for antimonial-resistant cases (Bern
et al., 2006; Croft, 2008, Olliaro et al., 2005). It is considered a secondline
drug for cutaneous or mucosal leishmaniasis, where it has been
shown effective for the treatment of immunocompromised patients
(Alvar et al., 2006). However, because cutaneous leishmaniasis is typically
self-limiting, the drug has not been evaluated for treatment of a
broader range of patient populations. The lipid preparations of the drug
have reduced toxicity, but the cost of the drug and the difficulty of
administration remain a problem in endemic regions.
The mechanism of action of amphotericin B against leishmania
is similar to the basis for the drug’s antifungal activities (Chapter 57).
Amphotericin complexes with ergosterol precursors in the cell membrane,
forming pores that allow ions to enter the cell. Leishmania
has similar sterol composition to fungal pathogens, and the drug
binds to these sterols preferentially over the host cholesterol. No significant
resistance to the drug has been encountered after nearly 30
years of use as an antifungal agent.
Therapeutic Uses. Numerous dosing schedules have been reported
for the treatment of visceral leishmaniasis, with most achieving high
cure rates and good safety (Alvar et al., 2006, Bern et al., 2006;
Olliaro et al., 2005). Typical schemes of 10-20 mg/kg total dose
given in divided doses over 10-20 days by intravenous infusion have
yielded >95% cure rates. In the U.S., the FDA recommends 3 mg/kg
intravenously on days 1-5, 14, and 21 for a total dose of 21 mg/kg
(Meyerhoff, 1999). Shorter courses of the drug have been tested with
good efficacy and provide a potential alternative with lower cost,
although only a limited number of patients have been tested: Cure
rates of 89-91% were observed for single doses of 3.75, 5, and
7.5 mg/kg. Recent data suggest that a single dose of 5 mg/kg followed
by 7-14 days treatment with oral miltefosine was effective at
curing visceral leishmaniasis, and this dosing scheme warrants additional
study (Sundar et al., 2008).
Chloroquine
The pharmacology and toxicology of chloroquine are presented in
Chapter 49 (anti-malarials). Chloroquine does have an FDAapproved
use for extra-intestinal amebiasis at a dose of 1 g (600 mg
base) daily for 2 days, followed by 500 mg daily for at least 2-3 weeks.
Treatment is usually combined with an effective intestinal amebicide.
The interested reader should consult the 11th edition of this
book for further details.
Diloxanide Furoate
Diloxanide furoate (FURAMIDE, others) is the furoate ester of diloxanide,
a derivative of dichloroacetamide. Diloxanide furoate is a very
effective luminal agent for the treatment of E. histolytica infection
but is no longer available in the U.S. The interested reader should
consult the 10th edition of this book for further details on this agent.
Eflornithine
Eflornithine (α-D,L difluoromethylornithine, DFMO,
ORNIDYL) is an irreversible catalytic (suicide) inhibitor
of ornithine decarboxylase, the enzyme that catalyzes
the first and rate-limiting step in the biosynthesis of
polyamines (Casero and Marton, 2007). The
polyamines—putrescine, spermidine, and in mammals,
spermine—are required for cell division and for normal
cell differentiation. In trypanosomes, spermidine additionally
is required for the synthesis of trypanothione,
which is a conjugate of spermidine and glutathione that
replaces many of the functions of glutathione in the parasite
cell (Fries and Fairlamb, 2003).
Both in animal models and in vitro, eflornithine arrests the
growth of several types of tumor cells, providing the basis for its
clinical evaluation as an antitumor agent. The discovery that eflornithine
cured rodent infections with T. brucei first focused attention
on protozoal polyamine biosynthesis as a potential target for
chemotherapeutic attack (Bacchi et al., 1980). Eflornithine currently
is used to treat West African (Gambian) trypanosomiasis caused by
T. brucei gambiense (Balasegaram et al., 2006a, 2009; Chappuis,