Page 936 - Basic _ Clinical Pharmacology ( PDFDrive )

922 SECTION VIII Chemotherapeutic Drugs

TABLE 52–4 WHO recommendations for the artemether (lipid-soluble; oral, intramuscular, and rectal administra-
treatment of falciparum malaria. tion), and dihydroartemisinin (water-soluble; oral administration).
Regimen Notes Chemistry & Pharmacokinetics
Artemether-lumefantrine Co-formulated; first-line therapy in Artemisinin and its analogs are complex 3- and 4-ring struc-
(Coartem, Riamet) many countries; approved in the USA
tures (Figure 52-2). They are rapidly absorbed, with peak plasma
Artesunate-amodiaquine Co-formulated; first-line therapy in levels occurring promptly. Half-lives after oral administration are
(ASAQ, Arsucam, Coarsucam) many African countries
30–60 minutes for artesunate and dihydroartemisinin, and 2–3 hours
Artesunate-mefloquine Co-formulated; first-line therapy in for artemether. Artemisinin, artesunate, and artemether are rapidly
parts of Southeast Asia and South
America metabolized to the active metabolite dihydroartemisinin. Drug levels
Dihydroartemisinin-pipera- Co-formulated; first-line therapy in appear to decrease after a number of days of therapy.
quine (Artekin, Duocotecxin) some countries in Southeast Asia
Artesunate-sulfadoxine- First-line therapy in some countries, Antimalarial Action & Resistance
pyrimethamine but efficacy lower than other
regimens in most areas The artemisinins are now widely available, but monotherapy for
the treatment of uncomplicated malaria is strongly discouraged.
Data from World Health Organization: Guidelines for the Treatment of Malaria, 3rd ed.
World Health Organization. Geneva, 2015. Rather, co-formulated artemisinin-based combination therapies
are recommended to improve efficacy and prevent the selection
of artemisinin-resistant parasites. The oral combination regimen
therapy for the treatment of uncomplicated falciparum malaria in Coartem (artemether-lumefantrine) was approved by the U.S.
many countries in Africa. Long-term chemoprophylaxis with amo- Food and Drug Administration (FDA) in 2009, and it may be
diaquine is best avoided because of its apparent increased toxicity considered the new first-line therapy in the USA for uncompli-
with long-term use, but short-term seasonal malaria chemopreven- cated falciparum malaria, although it may not be widely available.
tion with amodiaquine plus sulfadoxine-pyrimethamine (monthly Intravenous artesunate is available from the CDC; use is initiated
treatment doses for 3–4 months during the transmission season) is by contacting the CDC, which will release it for appropriate indi-
now recommended by the WHO for the Sahel sub-region of Africa. cations (falciparum malaria with signs of severe disease or inability
Piperaquine is a bisquinoline that was used widely to
treat chloroquine-resistant falciparum malaria in China in the to take oral medications) from stocks stored around the USA.
Artemisinin and its analogs are very rapidly acting blood schi-
1970s–1980s, but its use waned after resistance became widespread. zonticides against all human malaria parasites. Artemisinins have
More recently, piperaquine combined with dihydroartemisinin no effect on hepatic stages. They are active against young, but
(Artekin, Duocotecxin) showed excellent efficacy and safety for the not mature gametocytes. The antimalarial activity of artemisinins
treatment of falciparum malaria, although very recently decreased appears to result from the production of free radicals that follows the
efficacy has been seen in southeast Asia, linked to decreased activity iron-catalyzed cleavage of the artemisinin endoperoxide bridge. Arte-
of both components of the combination. Piperaquine has a longer misinin resistance is not yet a widespread problem, but delayed clear-
half-life (~28 days) than amodiaquine (~14 days), mefloquine ance of P falciparum infections and decreased treatment efficacy in
(~14 days), or lumefantrine (~4 days), leading to a longer period parts of Southeast Asia demonstrate a worrisome focus of resistance.
of post-treatment prophylaxis with dihydroartemisinin-piperaquine
than with the other leading artemisinin-based combinations; this
feature should be particularly advantageous in high-transmission Clinical Uses
areas. Dihydroartemisinin-piperaquine is now the first-line ther- Artemisinin-based combination therapy is now the standard of
apy for the treatment of uncomplicated falciparum malaria in care for treatment of uncomplicated falciparum malaria in nearly
some countries in Asia. As dihydroartemisinin-piperaquine offers all endemic areas. The leading regimens are highly efficacious,
extended protection against malaria, there is interest in chemopre- safe, and well tolerated. These regimens were developed because
vention with monthly dosing of the drug, which has shown excel- the short plasma half-lives of the artemisinins led to unaccept-
lent efficacy in children and pregnant women in Africa. ably high recrudescence rates after short-course therapy, which
were reversed by inclusion of longer-acting drugs. Combination
therapy also helps to protect against the selection of artemisinin
ARTEMISININ & ITS DERIVATIVES resistance. However, with completion of dosing after 3 days, the
artemisinin components are rapidly eliminated, and so selection of
Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide resistance to partner drugs is of concern.
(Figure 52–2), the active component of an herbal medicine that The WHO recommends five artemisinin-based combina-
has been used as an antipyretic in China for more than 2000 years. tions for the treatment of uncomplicated falciparum malaria
Artemisinin is insoluble and can only be used orally. Analogs have (Table 52–4). One of these, artesunate-sulfadoxine-pyrimethamine
been synthesized to increase solubility and improve antimalarial is not recommended in many areas owing to unacceptable levels
efficacy. The most important of these analogs are artesunate (water- of resistance to sulfadoxine-pyrimethamine, but it is the first-line
soluble; oral, intravenous, intramuscular, and rectal administration), therapy in some countries. The other recommended regimens are