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

and oocytes of C. parvum and inhibit the growth of the trophozoites
of G. intestinalis, E. histolytica, and T. vaginalis in vitro
(Adagu et al., 2002). Activity against other protozoans, including
Blastocystis hominis, Isospora belli, and Cyclospora cayetanensis
also has been reported. Nitazoxanide also demonstrated activity
against the intestinal helminths: Hymenolepis nana, Trichuris
trichiura, Ascaris lumbricoides, Enterobius vermicularis, Ancylostoma
duodenale, Strongyloides stercoralis, and the liver fluke
Fasciolahepatica. Effects against some anaerobic or microaerophilic
bacteria, including Clostridium spp. and H. pylori, also have been
reported. Nitazoxanide reportedly displays antiviral activity and is
now undergoing clinical trials for the treatment of hepatitis C
(Rossignol and Keeffe, 2008).
Mechanism of Action and Resistance. Nitazoxanide interferes with
the PFOR enzyme-dependent electron-transfer reaction, which is
essential to anaerobic metabolism in protozoan and bacterial species.
One proposed mechanism of nitazoxanide is blockade of the first
step in the PFOR chain by inhibiting the binding of pyruvate to the
thiamine pyrophosphate cofactor (Hoffman et al., 2007). Resistance
to nitazoxanide has been induced in Giardia in vitro, but clinically
resistant clinical isolates have not yet been reported.
Absorption, Fate, and Excretion. Following oral administration,
nitazoxanide is hydrolyzed rapidly to its active metabolite, tizoxanide,
which undergoes conjugation primarily to tizoxanide glucuronide.
Bioavailability after an oral dose is excellent, and maximum plasma
concentrations of the metabolites are detected within 1-4 hours following
administration of the parent compound. Tizoxanide is >99.9%
bound to plasma proteins. Tizoxanide is excreted in the urine, bile,
and feces; tizoxanide glucuronide is excreted in the urine and bile.
The pharmacokinetics of nitazoxanide in individuals with impaired
hepatic or renal function have not been reported.
Therapeutic Uses. In the U.S., nitazoxanide is approved for the treatment
of G. intestinalis infection (therapeutic efficacy of 85-90% for
clinical response) and for the treatment of diarrhea caused by cryptosporidia
(therapeutic efficacy, 56-88% for clinical response) in
adults and children >1 year of age (Amadi et al., 2002; Rossignol et
al., 2001). The efficacy of nitazoxanide in children (or adults) with
cryptosporidia infection and AIDS has not been clearly established.
For children ages 12-47 months, the recommended dose is 100 mg
nitazoxanide every 12 hours for 3 days; for children ages 4-11 years,
the dose is 200 mg nitazoxanide every 12 hours for 3 days. A 500-mg
tablet, suitable for adult dosing (every 12 hours), is available.
Nitazoxanide has been used as a single agent to treat mixed
infections with intestinal parasites (protozoa and helminths) in several
trials. Effective parasite clearance (based on negative follow-up fecal
samples) after nitazoxanide treatment was shown for G. intestinalis,
E. histolytica/E. dispar, B. hominis, C. parvum, C. cayetanensis, I.
belli, H. nana, T. trichiura, A. lumbricoides, and E. vermicularis
(Romero-Cabello et al., 1997), although more than one course of therapy
was required in some cases. Nitazoxanide may have some efficacy
against Fasciola hepatica infections (Favennec et al., 2003) and
has been used to treat infections with G. intestinalis that are resistant
to metronidazole and albendazole (Abboud et al., 2001).
Toxicity and Side Effects. To date, adverse effects appear to be rare
with nitazoxanide. Abdominal pain, diarrhea, vomiting, and
headache have been reported, but rates were no different from those
in patients receiving placebo. A greenish tint to the urine is seen in
most individuals taking nitazoxanide. Nitazoxanide is a pregnancy
Category B agent, based on animal teratogenicity and fertility studies,
but there is no clinical experience with its use in pregnant women
or nursing mothers.
Paromomycin
Paromomycin (aminosidine, HUMATIN) is an aminoglycoside
of the neomycin/kanamycin family (Chapter 54)
that is used as an oral agent to treat E. histolytica infection.
The drug is not absorbed from the GI tract and thus
the actions of an oral dose are confined to the GI tract.
Paromomycin also has been used orally to treat cryptosporidiosis
and giardiasis. A topical formulation has
been used to treat trichomoniasis, and parenteral administration
has been used for visceral leishmaniasis.
Mechanism of Action. Paromomycin shares the same mechanism of
action as neomycin and kanamycin (binding to the 30S ribosomal
subunit) and has the same spectrum of antibacterial activity.
Paromomycin is available only for oral use in the U.S. Following
oral administration, 100% of the drug is recovered in the feces, and
even in cases of compromised gut integrity, there is little evidence for
clinically significant absorption of paromomycin. Parenteral administration
carries the same risks of nephrotoxicity and ototoxicity seen
with other aminoglycosides.
Antimicrobial Effects; Therapeutics Uses. Paromomycin is the
drug of choice for treating intestinal colonization with E. histolytica.
It is used in combination with metronidazole to treat amebic colitis
and amebic liver abscess and can be used as a single agent for
asymptomatic individuals found to have E. histolytica intestinal
colonization. Recommended dosing for adults and children is
25-35 mg/kg per day orally in three divided doses. Adverse effects
are rare with oral usage but include abdominal pain and cramping,
epigastric pain, nausea and vomiting, steatorrhea, and diarrhea.
Rarely, rash and headache have been reported. Paromomycin has
been used to treat cryptosporidiosis in AIDS patients both as a single
agent and in combination with azithromycin, but in a randomized
controlled trial, paromomycin was no more effective than placebo
for this indication (Hewitt et al., 2000). Paromomycin has been advocated
as a treatment for giardiasis in pregnant women, especially
during the first trimester, when metronidazole is contraindicated and
as an alternative agent for metronidazole-resistant isolates of G.
intestinalis. Although there is limited clinical experience, response
rates of 55-90% have been reported (Gardner and Hill, 2001).
Dosing in adults is 500 mg orally three times daily for 10 days,
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CHAPTER 50
CHEMOTHERAPY OF PROTOZOAL INFECTIONS