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

1398 recent study reported an increased risk of neutropenia
with amodiaquine therapy in HIV patients receiving
antiretroviral therapy (Gasasira et al., 2008).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
In vivo, amodiaquine is rapidly converted by hepatic CYPs
into monodesethyl-amodiaquine. This metabolite, which retains
substantial antimalarial activity, has a plasma t 1/2
of 9-18 days and
reaches a peak concentration of ~500 nM 2 hours after oral administration.
By contrast, amodiaquine has a t 1/2
of ~3 hours, attaining
a peak concentration of ~25 nM within 30 minutes of oral administration
(Eastman and Fidock, 2009). In vivo clearance rates of amodiaquine,
however, display a variation between individuals that ranges
from 78 to 943 mL/min/kg.
Piperaquine, a potent and well-tolerated bisquinoline
compound (Figure 49–2) structurally related to
chloroquine, became the primary antimalarial in China
during the 1970s and 1980s in response to increasing
rates of chloroquine resistance.
Piperaquine has a large volume of distribution and reduced
rates of excretion after multiple doses. This lipophilic drug is rapidly
absorbed, with a T max
(time to reach the highest concentration) of 2
hours after a single dose. In clinical trials, the combination of piperaquine
and dihydroartemisinin produced cure rates and cleared fever
and parasites in a time frame similar to artesunate-mefloquine (Wells
et al., 2009). Piperaquine has the longest plasma t 1/2
(5 weeks) of all
ACT partner drugs, suggesting that piperaquine-dihydroartemisinin
might also be effective in reducing rates of reinfection following
treatment.
Pyronaridine, an antimalarial structurally related
to amodiaquine (Figure 49–2), was developed by the
Chinese in the 1970s.
Pyronaridine is well tolerated and highly potent against both
P. falciparum and P. vivax, causing fever to subside in 1-2 days and
parasite clearance in 2-3 days. Clinical data from trials of artesunatepyronaridine
should soon be available (Wells et al., 2009).
ATOVAQUONE
History. Based on the antiprotozoal activity of hydroxynaphthoquinones,
atovaquone (MEPRON) was developed
as a promising synthetic derivative with potent activity
against Plasmodium species and the opportunistic
pathogens Pneumocystis jiroveci (previously called
Pneumocystis carinii) and Toxoplasma gondii (Schlitzer,
2007). The FDA approved this compound in 1992 for
treatment of mild-to-moderate P. jiroveci pneumonia in
patients intolerant of trimethoprim-sulfamethoxazole.
Subsequent clinical studies in patients with uncomplicated
P. falciparum malaria revealed that atovaquone
produced good initial responses, but parasites recrudesced
and were highly atovaquone resistant. In contrast,
the combination of atovaquone and proguanil produced
high cure rates with minimal toxicity. A fixed combination
of atovaquone with proguanil hydrochloride
(MALARONE) is available in the U.S. for malaria chemoprophylaxis
and for the treatment of uncomplicated
P. falciparum malaria in adults and children (Boggild
et al., 2007).
Chemistry. Atovaquone is a highly lipophilic analog of
ubiquinone.
Mechanisms of Antimalarial Action and Resistance.
Atovaquone is highly active against P. falciparum asexual
blood stage parasites in vitro (with low nanomolar
activity) and in vivo in humans and the Aotus primate
model. This drug is effective against liver stages of P.
falciparum but not against P. vivax liver stage hypnozoites.
Atovaquone acts selectively on the mitochondrial
cytochrome bc 1
complex to inhibit electron transport
and collapse the mitochondrial membrane potential
(Vaidya and Mather, 2009). The primary function of
mitochondrial electron transport in P. falciparum is to
regenerate ubiquinone, which is the electron acceptor
for parasite dihydroorotate dehydrogenase, an enzyme
essential for pyrimidine biosynthesis in the parasite
(Painter et al., 2007). Synergy between proguanil and
atovaquone results from the ability of nonmetabolized
proguanil to enhance the mitochondrial toxicity of atovaquone
(Fivelman et al., 2004; Srivastava et al., 1999).
Resistance to atovaquone alone in P. falciparum develops easily
in vitro and in vivo, and it is conferred by single non-synonymous
nucleotide polymorphisms in the cytochrome b gene located in the
mitochondrial genome (Kessl et al., 2007). In the Saccharomyces
cerevisiae cytochrome bc 1
complex, atovaquone binding is inhibited
by the introduction of resistance mutations found in P. falciparum.
Similar mutations have been reported in resistant isolates of rodent
malarial species, as well as in T. gondii and perhaps P. jiroveci.
Addition of proguanil markedly reduces the frequency of appearance
of atovaquone resistance, as based on in vivo treatment cure rate.
However, once atovaquone resistance is present, the synergy of the
partner drug proguanil diminishes. In the key mutation associated
with clinical atovaquone-proguanil resistance, tyrosine is replaced
by serine, cysteine, or asparagine at codon 268 (Y268S/C/N) of the
cytochrome b gene. Reports of atovaquone-proguanil treatment