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

1450
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Table 51–1
Structure of the Benzimidazoles
R 1
R 2
DERIVATIVE
H— Thiabendazole
—NHCO 2
CH 3
Mebendazole
—NHCO 2
CH 3
CH 3
CH 2
CH 2
S— Albendazole
Brutto, 2000) and cystic hydatid disease (Horton, 1997). When used
in single dose in conjunction with either ivermectin or DEC, it has
shown additive effect in the control of lymphatic filariasis and related
tissue filarial infections (Molyneux and Zagaria, 2002; Molyneux et
al., 2003). Of note, albendazole lacks activity against the liver fluke
F. hepatica.
Anthelmintic Action. The primary mechanism of action
of BZ is thought to be inhibition of microtubule polymerization
by binding to β-tubulin (Prichard, 1994).
The selective toxicity of these agents against helminths
results from their higher affinity for parasite β-tubulin
than for the same target in higher eukaryotes. A range
of other biochemical changes are found in nematodes
following BZ exposure, including inhibition of mitochondrial
fumarate reductase, reduced glucose transport,
and uncoupling of oxidative phosphorylation,
Studies of BZ resistance by site-directed mutagenesis of the
β-tubulin gene in the free-living nematode Caenorhabditis elegans
(Driscoll et al., 1989) and of BZ resistance in the sheep nematode
Haemonchus contortus have provided insights into the mechanisms
of action of BZ drugs and of the mechanism of resistance (Prichard,
1994) In drug-resistant isolates of H. contortus, BZ drugs display
reduced affinity binding to β-tubulin and specific mutations occur
in the β-tubulin gene (Kwa et al., 1995; Roos, 1997). The major
mechanism of drug resistance in nematodes involves selection of a
naturally occurring “resistant” genotype entailing a Phe l Tyr
change at position 200 of β-tubulin (Sangster and Gill, 1999).
Evidence for the emergence of β-tubulin gene mutations associated
with resistance among human nematodes is confined to T.
trichuria (Diawara et al., 2009) and W. bancrofti (Schwab et al.,
2005). Drug treatment failures have been reported in hookworm
infections (Flohr et al., 2007), but there is little evidence of
widespread dissemination of resistant forms. However, these recent
observations, and the increasing use of BZs in parasite control
programs, suggest that monitoring for BZ resistance is critically
important, especially as veterinary experience indicates that
drug-resistant helminths can persist even after selection pressure is
withdrawn.
The BZs, exemplified by mebendazole and albendazole, are
versatile anthelmintic agents, particularly against GI nematodes,
where their action is not limited by a requirement for absorption.
Appropriate doses of mebendazole and albendazole are highly effective
in treating most of the major STH infections (ascariasis, enterobiasis,
trichuriasis, and hookworm) as well as less common human
nematode infections. These drugs are active against both larval and
adult stages of nematodes that cause these infections, and they are
ovicidal for Ascaris and Trichuris. Immobilization and death of susceptible
GI parasites occur slowly, and their clearance from the GI
tract may not be complete until several days after treatment.
Removal of STHs in children by a single-dose treatment with
either albendazole or mebendazole improves their health, as evidenced
by post-treatment catch-up growth and replenishment of
iron stores (Hotez et al, 2004, 2009). In addition, BZ treatment of
STH infections results in improvements in childhood intellectual
and cognitive development (Drake et al., 2000). These observations
have led to advocacy for the implementation of large-scale STH
control programs that target school-aged children (Hotez et al.,
2009; WHO, 2002).
Albendazole is superior to mebendazole in curing hookworm
and trichuriasis infections in children (de Silva et al., 2003), especially
when used as a single dose (Keiser and Utzinger, 2008).
Moreover, albendazole is more effective than mebendazole against
strongyloidiasis (Liu and Weller, 1993) and is superior to mebendazole
against all tissue-dwelling helminths due to its active metabolite
albendazole sulfoxide. It is therefore the drug of choice against
cystic and alveolar hydatid disease caused by Echinococcus granulosus
and E. multilocularis (Davis et al., 1989; Horton, 1997), and
neurocysticercosis caused by larval forms of Taenia solium (Evans
et al., 1997; Garcia and Del Brutto, 2000). The BZs probably are
active against the intestinal stages of Trichinella spiralis in humans
but probably do not affect the larval stages in tissues. Albendazole
is highly effective against the migrating forms of dog and cat hookworms
that cause cutaneous larval migrans, although thiabendazole
can be applied topically for this purpose. Microsporidial species that
cause intestinal infections in HIV-infected individuals respond partially
(Enterocytozoon bieneusi) or completely (Encephalitozoon
intestinalis and related Encephalitozoon species) to albendazole. The
sulfoxide metabolite of albendazole appears to be especially effective
against these parasites in vitro (Katiyar and Edlind, 1997).
Albendazole also has efficacy against anaerobic protozoa such as
Trichomonas vaginalis and Giardia lamblia (Ottesen et al., 1999).
Although BZs exert antifungal activity in vitro, they have no clinical
utility in human mycoses.
Absorption, Fate, and Excretion. Thiabendazole is soluble
in water; mebendazole and albendazole are poorly
soluble in aqueous solution. The low systemic bioavailability
(22%) of mebendazole results from a combination
of poor absorption and rapid first-pass hepatic
metabolism. Co-administration of cimetidine will
increase plasma levels of mebendazole, possibly due to