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

Table 49–4
Regimen for Presumptive Self-Treatment of Malaria
DRUG ADULT DOSE PEDIATRIC DOSE COMMENTS
Atovaquone/proguanil 4 tablets (each dose Daily dose to be taken Contraindicated in persons with severe
(MALARONE) contains 1000 mg for 3 consecutive days: renal impairment (creatinine clearance
Self-treatment drug atovaquone and 5-8 kg: 2 pediatric <30 mL/min). Not recommended for
to be used if 400 mg proguanil) tablets; self-treatment in persons on atovaquone/
professional medical orally as a single 9-10 kg: 3 pediatric proguanil prophylaxis. Not currently
care is not available daily dose for 3 tablets; recommended for children <5 kg,
within 24 hours. consecutive days. 11-20 kg: 1 adult tablet; pregnant women, and women breast-
Medical care should 21-30 kg: 2 adult tablets; feeding infants weighing <5 kg
be sought
31-40 kg: 3 adult tablets;
immediately after
>41 kg: 4 adult tablets
treatment.
These regimens are based on published recommendations of the United States Centers for Disease Control and Prevention (CDC). These recommendations
may change over time. Up-to-date information should be obtained from www.cdc.gov/travel. Recommendations and available treatment differ
among countries in the industrialized world, developing world, and malaria-endemic regions; in the latter, some antimalarial treatments may be
available without prescription but the most effective drugs usually will be controlled by governmental agencies.
Source: From http://wwwnc.cdc.gov/travel/content/yellowbook/home-2010.aspx. Accessed January 12, 2010.
The derivatives display improved potency and bioavailability
and have largely replaced the use of artemisinin. Dihydroartemisinin
is a reduced product, artesunate is the water-soluble hemisuccinate
ester of dihydroartemisinin, and artemether is a lipophilic methyl
ether. Extensive structure-activity studies have confirmed the requirement
for an endoperoxide moiety for antimalarial activity.
Mechanisms of Antimalarial Action and Resistance. As
a class, the artemisinins are very potent and fast-acting
antimalarials, inducing more rapid parasite clearance
and fever resolution than any other currently licensed
antimalarial drug. They are particularly well suited for
the treatment of severe P. falciparum malaria and are
also effective against the asexual erythrocytic stages
of P. vivax. Increasingly, the standard treatment of
malaria employs artemisinin-based combination therapies
(ACTs) to increase treatment efficacy and reduce
selection pressure for the emergence of drug resistance.
Artemisinins cause a significant reduction of the parasite
burden, with a four-log 10
reduction in the parasite
population for each 48-hour cycle of intraerythrocytic
invasion, replication, and egress. As such, only three to
four cycles (6-8 days) of treatment are required to
remove all the parasites from the blood (White, 2008).
Additionally, artemisinins possess some gametocytocidal
activity, leading to a decrease in malarial parasite
transmission. ACTs have low toxicity and are considered
safe for use in nonpregnant adults and children. Of
concern, however, is the widespread distribution of
counterfeit or clinically substandard drugs that contain
small quantities of the artemisinin derivative, a practice
that threatens the effective administration of ACTs.
The mechanisms by which ACTs exert their antimalarial
activity remain contentious (Golenser et al., 2006). Nevertheless,
most studies concur that the activity of artemisinin and its potent
derivatives results from reductive scission of the peroxide bridge by
reduced heme-iron, which is produced inside the highly acidic digestive
vacuole (DV) of the parasite as it digests hemoglobin. In addition
to the formation of potentially toxic heme-adducts, activated
artemisinin (for which the site of action remains unclear) might in
turn generate free radicals that alkylate and oxidize proteins and possibly
lipids in parasitized erythrocytes (Eastman and Fidock, 2009).
Artemisinins do not display significant clinical crossresistance
with other drugs. Indeed, sensitivity to artemisinins may
even be increased in at least some strains of chloroquine-resistant
parasites. Recent evidence has nonetheless suggested the emergence
of P. falciparum isolates with an increased tolerance to artemisinins,
manifesting as longer parasite clearance times (Dondorp et al.,
2009). This has triggered significant efforts to elucidate the mechanistic
basis of resistance and implement means to limit its spread.
The World Health Organization (WHO) and most authorities strenuously
recommend using artemisinins only in combination therapy,
both to increase treatment efficacy and prevent the emergence of
drug resistance.
Absorption, Fate, and Excretion. The semisynthetic artemisinins have
been formulated for oral (dihydroartemisinin, artesunate, and
artemether), intramuscular (artesunate and artemether), intravenous
(artesunate), and rectal (artesunate) routes. Bioavailability after oral
dosing typically is ≤30%. Although artemisinins rapidly achieve peak
serum levels; intramuscular administration of the lipid-soluble
artemether peaks in 2-6 hours, due to a depot effect at the injection