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

1426 nifurtimox used in combination with eflornithine (NECT) (Priotto,
2009). This new protocol uses a shortened course of eflornithine in
combination with oral nifurtimox, with dosing as follows: 400 mg/kg
per day given intravenously every 12 h by 2 h infusion for 7 days plus
nifurtimox (orally at 15 mg/kg per day in 3 divided doses [every 8 h])
for 10 days. This combination is logistically easier to administer and
it requires less eflornithine, which is expensive to synthesize.
Importantly, compared to eflornithine alone, NECT achieves a higher
cure rate (96.5% vs. 91.5%). NECT has been added to the WHO
essentials medicines list and is likely to become the front line treatment
for the indication. Drug combination may also reduce the potential for
eflornithine resistance to develop in the field. Given the paucity of
drugs available for the treatment of late stage disease, the development
of eflornithine resistance would represent a very serious problem.
Toxicity and Side Effects. Eflornithine is reported to cause adverse
reactions in most of the treated patients (Balasegaram et al., 2008;
Burri and Brun, 2003; Chappuis, 2007; Chappuis et al., 2005; Priotto
et al., 2006, 2008); however, they are generally reversible on withdrawal
of the drug. Abdominal pain, both mild and moderate, and
headache were the predominant complaints followed by reactions at
the injection sites. Tissue infections and pneumonia were also
observed. The most severe reactions reported for one study, with
numbers given for events classified as major, included fever peaks
(6%), seizures (4%), and diarrhea (2%) (Priotto et al., 2008). The
case fatality rate for eflornithine (~1.2%) is significantly lower than
for melarsoprol (4.9%), and overall eflornithine is superior to melarsoprol
with respect to both safety and efficacy. Reversible hearing
loss can occur after prolonged therapy with oral doses. Although this
has been a problem in the use of eflornithine for cancer chemotherapy,
hearing loss has not been observed during the treatment of
sleeping sickness.
Therapeutic doses of eflornithine are large and require coadministration
of substantial volumes of intravenous fluid. This
poses significant practical limitations in remote settings and can
cause fluid overload in susceptible patients. For NECT, the severe
adverse events were reduced compared to eflornithine alone (14% vs.
29%), and treatment related deaths were also fewer (0.7% vs. 2%)
(Priotto, 2009). Both NECT and eflornithine alone showed significantly
fewer treatment-related deaths than what has been reported
for melarsoprol. With eflornithine alone, most reported deaths were
due to septic shock. The typical side effects of eflornithine (diarrhea,
fever, infection, hypertension, and skin rash) were reduced in the
NECT arm of the study, however more patients experienced tremors,
nausea and vomiting.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Emetine and Dehydroemetine
The use of emetine, an alkaloid derived from ipecac (“Brazil root”),
as a direct-acting systemic amebicide dates from the early part of
the 20th century. Dehydroemetine (MEBADIN) has similar pharmacological
properties but is considered to be less toxic. Although both
drugs were once used widely to treat severe invasive intestinal amebiasis
and extraintestinal amebiasis, they have been replaced by
metronidazole, which is as effective and far safer. Thus, emetine and
dehydroemetine should not be used unless metronidazole is contraindicated.
In the U.S., dehydroemetine is available under an investigational
new drug protocol from the CDC drug service. Details of
the pharmacology and toxicology of emetine and dehydroemetine
are presented in the fifth and earlier editions of this book.
Fumagillin
Fumagillin (FUMIDIL B, others) is an acyclic polyene macrolide produced
by the fungus Aspergillus fumigatus.
Both fumagillin and its synthetic analog TNP-470 are toxic to
microsporidia, and fumagillin is used widely to treat the
microsporidian Nosema apis, a pathogen of honey bees. Fumagillin
and TNP-470 also inhibit angiogenesis and suppress tumor growth,
and TNP-470 is undergoing clinical trials as an anticancer agent
(Chapter 61). Human methionine-aminopeptidase-2 (MetAP2) has
been identified as the target for the drugs’ antitumor activity, and a
gene encoding MetAP2 has been identified in the genome of the
microsporidian parasite E. cuniculi.
Fumagillin is used topically to treat keratoconjunctivitis
caused by E. hellem at a dose of 3-10 mg/mL in a balanced salt suspension.
For the treatment of intestinal microsporidiosis caused by
E. bieneusi, fumagillin was used at a dose of 20 mg orally three times
daily for 2 weeks (Molina et al., 2002). Adverse effects of fumagillin
may include abdominal cramps, nausea, vomiting, and diarrhea.
Reversible thrombocytopenia and neutropenia also have been
reported (Molina et al., 2002). Fumagillin has not been approved for
the systemic treatment of microsporidia infection in the U.S.
8-Hydroxyquinolines
The halogenated 8-hydroxyquinolines iodoquinol (diiodohydroxyquin)
and clioquinol (iodochlorhydroxyquin) have been used as
luminal agents to eliminate intestinal colonization with E. histolytica.
Iodoquinol (YODOXIN) is the safer of the two agents and is the
only one available for use as an oral agent in the U.S. When used at
appropriate doses (never to exceed 2 g/day and duration of therapy
not greater than 20 days in adults), adverse effects are unusual.
However, the use of these drugs, especially at doses exceeding 2
g/day, for long periods is associated with significant risk. The most
important toxic reaction, which has been ascribed primarily to clioquinol,
is subacute myelo-optic neuropathy. This disease is a
myelitis-like illness that was first described in epidemic form (thousands
of afflicted patients) in Japan; only sporadic cases have been
reported elsewhere, but the actual prevalence is undoubtedly higher.
Peripheral neuropathy is a less severe manifestation of neurotoxicity
owing to these drugs. Administration of iodoquinol in high doses
to children with chronic diarrhea has been associated with optic atrophy
and permanent loss of vision.
Because of its superior adverse-event profile, paromomycin
is preferred by many authorities as the luminal agent used to treat
amebiasis; however, iodoquinol is a reasonable alternative.
Iodoquinol is used in combination with metronidazole to treat