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

been reported and higher doses of the drug are required to treat
African strains than to treat Brazilian strains of S. mansoni.
Metrifonate (trichlorfon) has been used with considerable success in
the treatment of S. haematobium infections, but the drug is not effective
against S. mansoni and S. japonicum. Metrifonate is relatively
inexpensive and can be combined with oxamniquine for treatment of
mixed infections with S. haematobium and S. mansoni.
The artemisinin derivative artemether (Chapter 49) shows
promise as an anti-schistosomal agent. Artemether targets the larval
schistosomula stages of the parasite. Clinical trials confirmed
that artemether (administered in an oral dose of 6 mg/kg once
every 2-3 weeks) significantly reduced the incidence and intensity
of schistosome infections without adverse reactions. In animals
harboring juvenile and adult schistosome worms, the combination
of artemether and praziquantel resulted in significantly reductions
of worm burden than each drug administered singly (Xiao et al.,
1985). There is concern, however, that widespread use of
artemether as an anthelmintic may induce drug-resistant malaria
in areas where multidrug resistant plasmodia still respond to
artemether therapy.
Paragonimus westermani and Other Paragonimus
Species. Lung flukes, including several Paragonimus
species, infect humans and carnivores; P. westermani is
the most common. Found in the Far East and on the
African and South American continents, these parasites
have two intermediate hosts: snails and crustaceans.
Humans become infected by eating raw or undercooked
crabs or crayfish. Disease is caused by reactions to adult
worms in the lungs or ectopic sites.
Praziquantel is effective, as is triclabendazole (EGATEN), in a
dose of 10 mg/kg daily for 3 days (Gao et al., 2003). Bithionol is
considered a second-line agent; it is available in the U.S. through
the Centers for Disease Control and Prevention (CDC).
Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis
felineus. These closely related trematodes exist in
the Far East (C. sinensis, “the Chinese liver fluke,” and
O. viverrini) and parts of Eastern Europe (O. felineus).
Metacercariae released from poorly cooked infected
cyprinoid fish mature into adult flukes that inhabit the
human biliary system. Heavy infections can cause
obstructive liver disease, inflammatory gallbladder
pathology associated with cholangiocarcinoma, and
obstructive pancreatitis.
One-day therapy with praziquantel is highly effective against
these parasites.
Fasciola hepatica. Humans are only accidentally
infected with F. hepatica, the large liver fluke that exists
worldwide and primarily affects herbivorous ruminants
such as cattle and sheep. Eating contaminated freshwater
plants such as watercress initiates the infection.
Migratory larvae penetrate the intestine, invade the liver
from the peritoneum, end eventually reside in the biliary
tract. The acute illness is characterized by fever,
urticaria, and abdominal symptoms, whereas chronic
infection resembles that caused by other hepatic flukes.
Unlike other flukes, Fasciola spp. do not respond to
praziquantel.
Triclabendazole, given as a single oral dose of 10 mg/kg, or
in cases of severe infection 20 mg/kg divided into two doses, is the
drug of choice for treatment of fascioliasis. In the U.S., this agent is
available only from the manufacturer (Novartis). The cure rate
among a cohort of Turkish patients was 78%, and the addition of
another course(s) increased this to 90%. No significant side effects
were reported (Saba et al., 2004). Bithionol was previously the recommended
drug.
Fasciolopsis buski, Heterophyes heterophyes,
Metagonimus yokogawai, Nanophyetus salmincola.
Obtained by eating contaminated water chestnuts and
other caltrops in Southeast Asia, F. buski is one of the
largest parasites causing human infection. Undercooked
fish transmit infection with the other, much smaller GI
trematodes that are widely distributed geographically.
Abdominal symptoms produced by reactions to these
flukes usually are mild, but heavy infections with F. buski
can cause intestinal obstruction and peritonitis.
Infections with all the intestinal trematodes respond well to
single-day therapy with praziquantel.
ANTHELMINTIC DRUGS
Benzimidazoles (BZ)
History. The discovery by Brown and coworkers that thiabendazole
possessed potent activity against GI nematodes sparked development
of the benzimidazoles as broad-spectrum anthelmintic agents against
parasites of importance in both veterinary and human medicine. Of
the hundreds of derivatives tested, those most therapeutically useful
have modifications at the 2 and/or 5 positions of the benzimidazole
ring system. Three compounds, thiabendazole, mebendazole, and
albendazole, have been used extensively for the treatment of human
helminth infections. The chemical structures of these drugs are
shown in Table 51–1.
Thiabendazole, which contains a thiazole at position 2, is
active against a wide range of nematodes that infect the GI tract.
However, its clinical value against these organisms has declined
markedly because of thiabendazole’s toxicity (particularly unwanted
central nervous system [CNS], liver, hypersensitivity, and visual side
effects) relative to that of other equally effective drugs.
Mebendazole, the prototype benzimidazole carbamate, was introduced
for the treatment of intestinal roundworm infections as a result
of research carried out >30 years ago. Albendazole is a newer benzimidazole
carbamate that is used worldwide, both for treatment of
intestinal nematodes and cestodes, but also because of the systemic
bioavailability of its sulphoxide metabolite against tissue-dwelling
nematodes and cestodes (Venkatesan, 1998). Albendazole has
become the drug of choice for treating cysticercosis (Garcia and Del
1449
CHAPTER 51
CHEMOTHERAPY OF HELMINTH INFECTIONS