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

1456 ivermectin (Molyneux et al., 2003), and there is interest in extending
biannual ivermectin coverage to the endemic regions of sub-Saharan
Africa. Annual doses of the drug are quite safe and substantially
reduce transmission of this infection (Boatin et al., 1998; Brown,
1998). How long such therapy should continue is unknown.
Resistance to ivermectin and the related agent moxidectin
have been reported in a variety of parasites of veterinary importance,
as have poor parasitological responses to ivermectin in the onchocerciasis
control program (Osei-Atweneboana et al., 2007). Recent laboratory
work with C. elegans has shown that exposure to increasing
doses of ivermectin resulted in the development of a stable multidrug
resistance phenotype with cross-resistance to the related drug moxidectin
and to other antihelmintics, levamisole and pyrantel, but not
albendazole (James and Davey, 2009). The potential for the development
of similar resistance in human parasites exists, particularly in
the setting of mass treatment campaigns.
Lymphatic Filariasis. Initial studies indicated that single annual doses
of ivermectin (400 μg/kg) was both effective and safe for mass
chemotherapy of infections with W. bancrofti and B. malayi (Ottesen
and Ramachandran, 1995). Ivermectin is as effective as DEC for
controlling lymphatic filariasis, and unlike DEC, it can be used in
regions where onchocerciasis, loiasis, or both are endemic. Although
ivermectin as a single agent can reduce W. bancrofti microfilaremia,
the duration of treatment required to eliminate LF at 65% coverage
of the affected population presumably would be >6 years (Molyneux
et al., 2003). More recent evidence indicates that a single annual
dose of ivermectin (200 μg/kg) and a single annual dose of albendazole
(400 mg) are even more effective in controlling lymphatic filariasis
than either drug alone (www.filariasis.org). The duration of
treatment is at least 5 years, based on the estimated fecundity of the
adult worms. This dual-drug regimen also reduces infections with
intestinal nematodes. Facilitated by corporate donation of ivermectin
and albendazole, the drug combination now serves as the treatment
standard for mass chemotherapy and control of lymphatic filariasis
(Ottesen et al., 1999).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Strongyloidiasis. Ivermectin administered as a single dose of 150 to
200 μg/kg is the drug of choice for treatment of human strongyloidiasis
(Marti et al., 1996). It is at least as active as the older drug of choice,
thiabendazole, and significantly better tolerated. It is generally recommended
that a second dose be administered a week following the first
dose. It is more efficacious than a 3-day course of albendazole (Marti et
al., 1996). In the life-threatening Strongyloides hyperinfection syndrome
where GI absorption of oral dose may be poor, parenteral veterinary
ivermectin has been administered “off-label” to human subjects by the
subcutaneous route (Chiodini et al., 2000).
Infections with Other Intestinal Nematodes. Ivermectin also is variably
effective against other intestinal nematodes. It is more effective
in ascariasis and enterobiasis than in trichuriasis or hookworm infection
(Keiser and Utzinger, 2008). In the latter two infections, although
it is not curative, it significantly reduces the intensity of infection.
Other Indications. Although ivermectin has activity against microfilaria
(but not adult worms) of L. loa and M. ozzardi, it is not used
clinically to treat infections with these parasites. Taken as a single
200-μg/kg oral dose, ivermectin is a first-line drug for treatment of
cutaneous larva migrans caused by dog or cat hookworms.
Ivermectin, administered orally in a dose of 200 μg/kg, is an effective
treatment of scabies. In uncomplicated scabies, two doses should
be administered, 1-2 weeks apart. It should be used in severe
(crusted) scabies in repeated doses, with one recommended regimen
entailing 7 doses of 200 μg/kg given with food, on days 1, 2, 8, 9, 15,
22, and 29 (Roberts et al., 2005). The drug appears to be effective
against human head lice as well.
Toxicity, Side Effects, and Precautions. Ivermectin is well tolerated by
uninfected humans.
In filarial infection, ivermectin therapy frequently causes a
Mazzotti-like reaction to dying microfilariae. The intensity and
nature of these reactions relate to the microfilarial burden. After
treatment of O. volvulus infections, these side effects usually are limited
to mild itching and swollen, tender lymph nodes, which occur
in 5-35% of people, last just a few days, and are relieved by aspirin
and antihistamines (Goa et al., 1991). Rarely, more severe reactions
occur that include high fever, tachycardia, hypotension, prostration,
dizziness, headache, myalgia, arthralgia, diarrhea, and facial and
peripheral edema; these may respond to glucocorticoid therapy.
Ivermectin induces milder side effects than does DEC, and unlike
the latter, it seldom exacerbates ocular lesions in onchocerciasis. The
drug can cause rare but serious side effects including marked disability
and encephalopathies in patients with heavy L. loa microfilaria
(Gardon et al., 1997). Loa encephalopathy is associated with
ivermectin treatment of individuals with Loa microfilaremia levels
≥30,000 microfilariae per milliliter of blood (Molyneux et al., 2003).
There is little evidence that ivermectin is teratogenic or carcinogenic.
Possible adverse interactions of ivermectin with other drugs
that are extensively metabolized by hepatic CYP3A4 have yet to be
evaluated. Because of its effects on GABA receptors in the CNS, ivermectin
is contraindicated in conditions associated with an impaired
blood-brain barrier (e.g., African trypanosomiasis and meningitis).
Ivermectin is not approved for use in children <5 years of age or in
pregnant women. Lactating women taking the drug secrete low levels
in their milk; the consequences for nursing infants are unknown.
Currently, the WHO recommends against ivermectin treatments in
mass drug administration campaigns for pregnant women, lactating
women in the first week after birth, children <90 cm in height (~15 kg
in body weight), and the severely ill (WHO, 2006).
Praziquantel
Praziquantel (BILTRICIDE, DISTOCIDE) is a pyrazinoisoquinoline
derivative developed after this class of compounds
was discovered to have anthelmintic activity in
1972. The (–) isomer is responsible for most of the
drug’s anthelmintic activity.
The drug shows useful activity against most cestodes and
trematodes that infect humans, whereas nematodes generally are
unaffected (Andrews, 1985; Symposium, 1981). The drug is best
studied and most commonly used for treatment of schistosomiasis,
caused by S. mansoni, S. haematobium, and S. japonicum.