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

Anthelmintic Action. After rapid and reversible uptake,
praziquantel has two major effects on adult schistosomes.
At the lowest effective concentrations, it causes
increased muscular activity, followed by contraction
and spastic paralysis. Affected worms detach from
blood vessel walls and migrate from the mesenteric
veins to the liver. At slightly higher concentrations,
praziquantel causes tegumental damage and exposes a
number of tegumental antigens (Redman et al., 1996).
The clinical efficacy of this drug correlates better with
tegumental action (Xiao et al., 1985). The drug is ineffective
against juvenile schistosomes and therefore is
relatively ineffective in early infection. An intact
immune response is believed to be important for the
clinical efficacy of the drug.
The primary site of action of praziquantel is uncertain
(Aragon et al., 2009). The drug may act through generation of reactive
oxygen species. It also promotes an influx of Ca 2+ , and possibly
interacts with the variant Ca 2+ channel Ca-varβ (Jeziorski and
Greenberg, 2006), which is found in schistosomes and other
praziquantel-sensitive parasites. However, Ca 2+ influx does not correlate
with sensitivity to the drug an all settings (Pica-Mattoccia
et al., 2008). Prazifuantel inhibits adenosine flux (Angelucci et al.,
2007), but definitive evidence that this action contributes to the
anthelmintic effect is lacking.
Absorption, Fate, and Excretion. Praziquantel is readily absorbed
after oral administration, the drug reaching maximal levels in
human plasma in 1-2 hours. The pharmacokinetics of praziquantel
are dose related. Extensive first-pass metabolism to many inactive
hydroxylated and conjugated products limits the bioavailability of
this drug and results in plasma concentrations of metabolites at
least 100-fold higher than that of praziquantel. The drug is ~80%
bound to plasma proteins. Its plasma t 1/2
is 0.8-3 hours, depending
on the dose, compared with 4-6 hours for its metabolites; this may
be prolonged in patients with severe liver disease, including those
with hepatosplenic schistosomiasis. About 70% of an oral dose of
praziquantel is recovered as metabolites in the urine within 24
hours; most of the remainder is metabolized in the liver and eliminated
in the bile.
Therapeutic Uses. Praziquantel is approved in the U.S.
for therapy of schistosomiasis and liver fluke infections.
However, the drug has activity against many other
trematodes and cestodes. Praziquantel should be stored
at temperatures <30°C and swallowed with water without
chewing because of its bitter taste.
Praziquantel is the drug of choice for treating schistosomiasis
caused by all Schistosoma species that infect humans. Although
dosage regimens vary, a single oral dose of 40 mg/kg or three doses
of 20 mg/kg each, given 4-6 hours apart, generally produce cure rates
of 70-95% and consistently high reductions (>85%) in egg counts.
Tablets of 600 mg currently are available from generic manufacturers;
on average, treatment of a school-aged child in Africa
requires 2.5 tablets (WHO, 2002).
The absence of weighing scales in Africa and elsewhere in
developing countries led to the development dosing in proportion to
height (WHO 2006; www.who.int/wormcontrol).
Strains of S. mansoni and S. japonicum resistant to praziquantel
have been selected in laboratory studies (Fallon et al., 1996).
Moreover, decreased clinical efficacy of praziquantel against infections
with S. mansoni has been reported in two human populations
(Ismail et al., 1999). However, praziquantel-tolerant or -resistant
schistosome strains are not currently of clinical importance (Fallon
et al., 1996).
Three doses of 25 mg/kg taken 4-8 hours apart on the same
day result in high rates of cure for infections with either the liver
flukes Clonorchis sinensis and Opisthorchis viverrini, or the intestinal
flukes Fasciolopsis buski, Heterophyes heterophyes, and
Metagonimus yokogawai. The same three-dose regimen, used over
2 days, is highly effective against infections with the lung fluke,
Paragonimus westermani. Of note, the liver fluke Fasciola hepatica
is resistant to praziquantel and should be treated with the BZ drug triclabendazole.
Low doses of praziquantel can be used successfully to treat intestinal
infections with adult cestodes, for example, a single oral dose of
25 mg/kg for Hymenolepis nana and 10 to 20 mg/kg for
Diphyllobothrium latum, Taenia saginata, or T. solium. Retreatment after
7-10 days is advisable for individuals heavily infected with H. nana.
Although albendazole is preferred for therapy of human cysticercosis,
praziquantel represents an alternative agent, but its use for this indication
is hampered by the important pharmacokinetic interaction with dexamethasone
and other corticosteroids that should be co-administered in
this condition (Evans et al., 1997). Neither the “cystic” nor “alveolar”
hydatid disease caused by larval stages of Echinococcus tapeworms
responds to praziquantel, but the drug may have a role in the uncommon
setting of perioperative cyst spillage (Horton, 1997; Schantz, 1999).
Toxicity, Precautions, and Interactions. Abdominal discomfort, particularly
pain and nausea, diarrhea, headache, dizziness, and drowsiness
may occur shortly after taking praziquantel; these direct effects
are transient and dose related. Indirect effects such as fever, pruritus,
urticaria, rashes, arthralgia, and myalgia are noted occasionally. Such
side effects and increases in eosinophilia often relate to parasite burden
and are therefore believed to be a consequence of parasite killing
and antigen release. In neurocysticercosis, inflammatory reactions
to praziquantel may produce meningismus, seizures, mental changes,
and cerebrospinal fluid pleocytosis. These effects usually are delayed
in onset, last 2-3 days, and respond to appropriate symptomatic therapy
such as analgesics and anticonvulsants.
Praziquantel is considered safe in children >4 years of age
(or >94 cm in height), who probably tolerate the drug better than
adults. Low levels of the drug appear in the breast milk, but there is
no evidence that this compound is mutagenic or carcinogenic. High
doses of praziquantel increase abortion rates in rats, but a retrospective
study showed that treatment of pregnant women in Sudan
resulted in no significant differences between treated and untreated
women in the rates of abortion or preterm deliveries. Moreover, no
congenital abnormalities were noted by clinical examination in any
of the infants born to either group (Adam et al., 2004).
The bioavailability of praziquantel is reduced by inducers of
hepatic CYPs such as carbamazepine and phenobarbital; predictably,
co-administration of the CYP inhibitor, cimetidine, has the opposite
effect (Dachman et al., 1994). Dexamethasone reduces the
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CHAPTER 51
CHEMOTHERAPY OF HELMINTH INFECTIONS