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

1458 bioavailability of praziquantel. Under certain conditions, praziquantel
may increase the bioavailability of albendazole (Homeida et al., 1994).
Praziquantel is contraindicated in ocular cysticercosis
because the host response can irreversibly damage the eye. Shortly
after taking the drug, driving, operating machinery, and other tasks
requiring mental alertness should be avoided. Severe hepatic disease
can prolong the t 1/2
of praziquantel, requiring dosage adjustment in
such patients (Mandour et al., 1990).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Metrifonate
Metrifonate (trichlorfon; BILARCIL) is an organophosphorus
compound used first as an insecticide and later
as an anthelmintic, especially for treatment of
Schistosoma haematobium.
Metrifonate is a prodrug; at physiological pH, it is converted
nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethyl phosphate,
DDVP), a potent cholinesterase inhibitor (Chapter 10)
However, inhibition of cholinesterase alone is unlikely to explain the
antischistosomal properties of metrifonate (Bloom, 1981). In vitro,
dichlorvos is about equally potent as an inhibitor of both S. mansoni
and S. haematobium acetylcholinesterases, yet metrifonate is
effective clinically only against infections with S. haematobium. The
molecular basis for this species-selective effect is not understood.
Trichlorfon is the formulation of metrifonate approved for veterinary
purposes in the U.S. More complete information on the pharmacology
and therapeutic uses of metrifonate can be found in the
tenth edition of this book.
Oxamniquine
Oxamniquine is a 2-aminomethyltetrahydroquinoline derivative that
is used as a second-line drug after praziquantel for the treatment of
Schistosoma mansoni infection. S. haematobium and S. japonicum
are refractory to this drug. Although it has largely been
replaced by praziquantel and is not commercially available in the
U.S., it continues to be used in S. mansoni control programs, especially
in South America. More details on the pharmacology and
therapeutic uses of oxamniquine can be found in the ninth edition
of this book.
Niclosamide
Niclosamide, a halogenated salicylanilide derivative, was introduced
in the 1960s for human use as a taeniacide. This compound was considered
as a second-choice drug to praziquantel for treating human
intestinal infections with Taenia saginata, Diphyllobothrium latum,
Hymenolepis nana, and most other cestodes because it was cheap,
effective, and readily available in many parts of the world. However,
therapy with niclosamide poses a risk to people infected with T. solium
because ova released from drug-damaged gravid worms develop into
larvae that can cause cysticercosis, a dangerous infection that responds
poorly to chemotherapy. Niclosamide is no longer approved for use
in the U.S. More complete information on the pharmacology and
therapeutic uses of niclosamide can be found in the ninth edition of
this book.
Piperazine
Piperazine, a cyclic secondary amine, has been superseded as a firstline
anthelmintic by the better tolerated and more easily administered
benzimidazole anthelmintics (BZs). Piperazine is highly
effective against Ascaris lumbricoides and Enterobius vermicularis.
The predominant effect of piperazine on Ascaris is a flaccid paralysis
that results in expulsion of the worm by peristalsis. Affected
worms recover if incubated in drug-free medium. Piperazine acts as
a GABA-receptor agonist. By increasing chloride ion conductance
of Ascaris muscle membrane, the drug produces hyperpolarization
and reduced excitability that leads to muscle relaxation and flaccid
paralysis (Martin, 1985). Piperazine and dipiperazine are licensed
as veterinary medications in the U.S. More complete information on
the pharmacology and therapeutic uses of piperazine may be found
in the tenth edition of this book.
Pyrantel Pamoate
Pyrantel pamoate first was introduced into veterinary
practice as a broad-spectrum anthelmintic directed
against pinworm, roundworm, and hookworm infections.
Its effectiveness and lack of toxicity led to its trial
against related intestinal helminths in humans. Oxantel
pamoate, an m-oxyphenol analog of pyrantel, is effective
for single-dose treatment of trichuriasis.
Antihelmintic Action. Pyrantel and its analogs are depolarizing
neuromuscular blocking agents. They open nonselective cation channels
and induce persistent activation of nicotinic acetylcholine receptors
and spastic paralysis of the worm (Robertson et al., 1994).
Pyrantel also inhibits cholinesterases. It causes a slowly
developing contracture of isolated preparations of Ascaris at 1% of
the concentration of acetylcholine required to produce the same
effect. Pyrantel exposure leads to depolarization and increased spikedischarge
frequency, accompanied by increases in tension, in isolated
helminth muscle preparations. Pyrantel is effective against
hookworm, pinworm, and roundworm but is ineffective against
Trichuris trichiura, which responds paradoxically to the analog
oxantel.
Absorption, Fate, and Excretion. Pyrantel pamoate is poorly
absorbed from the GI tract, a property that confines its action to
intralumenal GI nematodes. Less than 15% is excreted in the urine
as parent drug and metabolites. The major proportion of an administered
dose is recovered in the feces.