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The first edition of the WHO Guidelines for the treatment of malaria was published in 2006. It recommended artemisinin combination therapy (ACT) for the treatment of both uncomplicated Plasmodium falciparum and vivax malaria. Recommended combinations were artemether plus lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine and artesunate plus sulfadoxine-pyrimethamine. Most of these were available as fixed-dose combinations, and the manufacture of single-agent artemisinin derivatives was discouraged. The second edition of the guidelines in 2010 introduced a new fifth ACT, dihydroartemisinin plus piperaquine (DHA + PPQ). Antimalarial therapy had been revolutionized by the introduction of the artemisinin derivative drugs in the 1990s from China.
These drugs chemically purified from Artemisia annua plants had a novel chemical structure, a sesquiterpene lactone (STL) ring and a novel mechanism of action, which is still not fully understood. It is thought that their activity (and toxicity) is based on reduction of the peroxide bridge with the generation of reactive free radicals [1-4]. The parent compounds artemisinin (molecular weight 282.33 g/mol), artemether (mw 298.38 g/mol) and artesunate (mw 384.42 g/mol) are metabolized to the main active compound DHA (mw 284.34 g/mol) (Figure 1). Other compounds containing various parts of the ring structure are active in vitro against malaria and some other infections such as cytomegalovirus [5] and toxoplasma [6]. These include other endoperoxides and trioxanes discussed below [7,8].
Figure 1. Qing hao su or artemisinin 1 and derivatives dihydroartemisinin 2, artemether 3, arteether 4, artesunic acid (artesunate) 5 and artelinate 6. The numbering scheme is that used by Chemical Abstracts.
(Figure omitted. See article PDF.)
Artemisinin monotherapy must be taken for 7 days (two and a half life cycles of the parasite) for effective cure rates. However, most people do not finish the course especially as they usually feel well within 48 h. A 3-day regimen is generally regarded most effective [9]. Therefore, it was proposed that they should only be given in combination with another longer acting antimalarial drug. There is clear evidence that combinations improve efficacy without increasing toxicity [10] and are cost-effective in economic models [11].
The choice of companion drug was mainly from existing classes. Historically antimalarial therapy had been dependent upon monotherapy, with drugs belonging to either the quinoline (chloroquine (CQ), quinine, mefloquine, primaquine and...