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

1414 For clinical classification of drug resistance, see
Bloland (2001). In endemic settings, recrudescence of
P. falciparum clinical episodes or asymptomatic parasitemia
after appropriate treatment can also be due to
reinfection.
For uncomplicated malaria caused by chloroquineresistant
P. falciparum (suspected either from travel history
or lack of response to chloroquine) or by a species
not yet identified, four treatment options are available:
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
• Artemether-lumefantrine
• Atovaquone-proguanil
• Oral quinine given along with other effective but
slower-acting blood schizonticides such as tetracyclines
(preferably doxycycline) or clindamycin
• Mefloquine
The oral route of drug administration is preferred,
but intravenous preparations may be administered
until oral medication can be taken. Malaria
caused by chloroquine-resistant P. vivax can be treated
by mefloquine, atovaquone-proguanil, or quinine (plus
tetracyclines), all combined with a course of primaquine.
Treatment of Severe Malaria. For severe malaria (see
Table 49–5 for diagnostic criteria), whatever the region
where the infection was acquired, the recommended treatments
are based on intravenous artesunate or quinidine
plus a second drug (Figure 49–4). Artesunate, now available
in the U.S. from the CDC under an investigational
new drug protocol, should be followed by atovaquoneproguanil,
clindamycin, or mefloquine. Quinidine must
be substituted for quinine (no longer available) and combined
with doxycycline, tetracycline, or clindamycin
(reviewed in Griffith et al., 2007). Exchange transfusion
may be of additional value in severe P. falciparum malaria
with high levels of parasitemia (Griffith et al., 2007;
Miller et al., 1989).
Children and pregnant women are the most susceptible to
severe malaria. With appropriate dosage adjustments and safety precautions,
the treatment of children generally is the same as for adults
(pediatric dose should never exceed adult dose). However, tetracyclines
should not be given to children <8 years of age except in an
emergency, and atovaquone-proguanil as treatment has been
approved only for children weighing >5 kg (for current information,
see the CDC website and Boggild et al., 2007).
Chemoprophylaxis and Treatment During Pregnancy.
Pregnant women should be urged not to travel to endemic
areas if possible (Freedman, 2008). Chemoprophylaxis
during pregnancy is complex, and women should evaluate
with expert medical staff the benefits and risks of different
strategies with regard to their particular situation.
Severe malaria during pregnancy should be treated with
intravenous antimalarial treatment according to the general
guidelines for severe malaria, taking into account the
drugs that should be avoided during pregnancy.
Among the antimalarial treatments available in the U.S.,
many should not be used during pregnancy because of lack of sufficient
formal safety data (antifolates, atovaquone-proguanil, and
artemether-lumefantrine) or known potential risks for the fetus (tetracycline,
doxycycline, primaquine, and mefloquine). The recommended
treatment of uncomplicated malaria during pregnancy relies
on chloroquine in areas with chloroquine-sensitive parasites, and
quinine, alone (in P. vivax infections) or in combination with clindamycin
(in P. falciparum infections), in areas with chloroquineresistant
parasites. Appropriate caution should be exercised when
administering quinine, given the frequency of hypoglycemia as an
adverse reaction in pregnant women. Pregnant patients with P. vivax
or P. ovale infections should be kept under chloroquine chemoprophylaxis
until delivery. After delivery, and after verifying that the
patient is not G6PD deficient, treatment with primaquine should be
initiated to eradicate hypnozoites. Atovaquone-proguanil and
artemether-lumefantrine are not indicated because of lack of safety
data. Mefloquine is also not indicated because of a possible association
with increased risk of stillbirth. However, if recommended
treatments are not available, these alternative options should be considered
after balancing the potential benefits and risks for the fetus.
A recent study demonstrated better outcomes when pregnant
women were treated with artesunate-atovaquone-proguanil compared
with quinine; however, adequate safety data for the developing fetus
are lacking (for review, see Dellicour et al., 2007). Another clinical
trial recently showed that a standard six-dose oral artemetherlumefantrine
regimen was well tolerated and safe in pregnant women
with uncomplicated falciparum malaria, but efficacy was inferior to
7-day artesunate monotherapy and was unsatisfactory for general
deployment along the Thai Cambodian border, probably resulting
from low drug concentrations in later pregnancy (McGready et al.,
2008). The use of antimalarial drugs in pregnancy has been well
reviewed (Ward et al., 2007).
In lactating mothers, treatment with most compounds is
acceptable, although chloroquine and hydroxychloroquine are the
preferred agents. The use of atovaquone-proguanil is not recommended
unless breast-feeding infants weigh >5 kg. Also, the breastfeeding
infant should be shown to have a normal G6PD level before
receiving primaquine (Schlagenhauf and Petersen, 2008).
New Targets, New Drugs
In the face of evolving drug resistance and the necessity to increase
the useful life span of antimalarial drugs through combination therapies,
novel and potent antimalarial drugs are urgently needed. The
malaria research pipeline includes either compounds derived from
known antimalarials through modification of their chemical structure
(likely to retain activity against the original targets), drugs previously
developed for other infectious organisms or diseases (and likely
act on the same target in Plasmodium), or inhibitors of novel targets
(exploiting differences in the biology of host and parasite). This
latter strategy of drug discovery benefits from the genome sequencing
projects of the different Plasmodium species and the human host.
Perspectives in malaria chemotherapy (including new drug targets