Review

# Qinghaosu (Artemisinin): The Price of Success

See allHide authors and affiliations

Science  18 Apr 2008:
Vol. 320, Issue 5874, pp. 330-334
DOI: 10.1126/science.1155165

## Abstract

Artemisinin and its derivatives have become essential components of antimalarial treatment. These plant-derived peroxides are unique among antimalarial drugs in killing the young intraerythrocytic malaria parasites, thereby preventing their development to more pathological mature stages. This results in rapid clinical and parasitological responses to treatment and life-saving benefit in severe malaria. Artemisinin combination treatments (ACTs) are now first-line drugs for uncomplicated falciparum malaria, but access to ACTs is still limited in most malaria-endemic countries. Improved agricultural practices, selection of high-yielding hybrids, microbial production, and the development of synthetic peroxides will lower prices. A global subsidy would make these drugs more affordable and available. ACTs are central to current malaria elimination initiatives, but there are concerns that tolerance to artemisinins may be emerging in Cambodia.

In the fourth decade of the 17 century, Jesuits brought the bark of a Peruvian tree (later named Cinchona) to Europe. This provided for the first time a specific remedy for agues, periodic fevers that were prevalent throughout much of the continent, particularly in and around marshy areas (mal-aria or bad air). In 1880, Alphonse Laveran identified the intraerythrocytic protozoan parasite that caused malaria. The Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) were shown to arrest the development of the malignant tertian malaria parasites (Plasmodium falciparum) at the mature trophozoite stage (after the first third of their 2-day intraerythrocytic life cycle) and thereby prevent their multiplication in the red blood cells (Fig. 1). Today, the Cinchona alkaloids are giving way to the products of a ubiquitous annual shrub (Artemesia annua, or huang hua hao, but often called qinghao) (Fig. 2).

The antimalarial properties of the traditional Chinese medicine qinghaosu (artemisinin) were discovered by Chinese scientists in 1971 who performed low temperature ethyl ether extractions of Artemesia annua. In a research effort, apparently prompted by the requests of Ho Chi Minh to Zhou En Lai for antimalarial drugs to protect his Vietnamese troops, the scientists identified the active antimalarial principle, characterized its physicochemical properties, conducted in vitro, animal, and human studies, and synthesized derivatives of the more potent dihydroartemisinin (DHA). Artemisinin was first announced to the rest of the world in 1979 (1). At first, biological chemists were puzzled by the apparent stability of the hitherto unknown 15-carbon (sesquiterpene) peroxide structure. A full chemical synthesis was reported 4 years later (2), although, as for quinine, this remains too expensive for commercialization. Trials reporting efficacy in both uncomplicated and severe malaria soon followed (3, 4), but progress thereafter was slow. Instead of accepting the compounds the Chinese had developed, the World Health Organization (WHO)–Special Program for Research and Training in Tropical Diseases (TDR), the pharmaceutical industry, and the U.S. Army elected to develop their own compounds. Time and money was wasted developing artemotil (arteether), the ethyl ether of DHA, an oil-based formulation for intramuscular injection, which the Chinese scientists had discarded earlier in favor of the almost identical artemether (the methyl ether of DHA) (Fig. 3). Initially, the orally active compounds and the water-soluble artesunate, which could be given intravenously, were neglected entirely outside China, but with worsening resistance to all available antimalarials in Southeast Asia, researchers there began to investigate the compounds from China, and an increasing evidence base accumulated supporting the rapidity, reliability, and safety of these drugs in both uncomplicated and severe malaria. The parent drug artemisinin was largely replaced by DHA and its derivatives artesunate and artemether, which have greater antimalarial activity (Fig. 2). Initially artemisinin and its derivatives were used as monotherapies, but it became gradually accepted that antimalarials, like antituberculosis and antiretroviral drugs, should be used in combination (5, 6). A semisynthetic artemisinin derivative (artelinate) was developed, but was not taken beyond animal studies, and another (artemisone) is under development. Artiflene, a structurally dissimilar peroxide derivative of another Chinese plant (yinghaosu) was developed in the early 1990s and proved an effective antimalarial in clinical trials, but it was eventually abandoned because of high production costs and lack of evident advantages over the artemisinin derivatives.

## Pharmacological Properties

Artemisinins kill nearly all of the asexual stages of parasite development in the blood (7), and also affect the sexual stages of P. falciparum (gametocytes), which transmit the infection to others (8), but they do not affect pre-erythrocytic development or the latent stages of P. vivax and P. ovale in the liver (the hypnozoites). The mechanism of action of artemisinins remains uncertain. The integrity of the endoperoxide bridge is necessary (but not sufficient) for antimalarial activity. Ion-dependent alkylation (principally by Fe++) is a likely mode of action (9), and the sarcoplasmic endoplasmic reticulum calcium adenosine triphosphatase (PfATPase 6) has been proposed as the primary target (10). The role of reactive decomposition intermediates such as carbon-centered free radicals remains controversial. The report that P. falciparum parasites from French Guiana with point mutations in the gene encoding PfATPase 6 were relatively resistant to artemether seemed to have fulfilled the molecular Koch's postulates for this target (11), but these findings have not yet been reproduced elsewhere. The synthetic peroxide trioxolanes, which are potent antimalarials, are 2 to 3 orders of magnitude less active in inhibiting PfATPase 6 (12).

Artemisinin's broad stage specificity of antimalarial action (Fig. 1) has two therapeutic consequences. Killing young circulating ring-stage parasites in P. falciparum infections results in a more rapid reduction in parasitaemia compared with other antimalarials (Fig. 4) and reduces considerably the number of parasites that mature to sequester in and block capillaries and venules (13, 14). This explains the rapidity of clinical responses and the life-saving benefit in severe malaria compared with quinine (which does not stop sequestration because it kills parasites only after they have matured and adhered to vascular endothelium). Reducing gametocyte carriage diminishes the transmission potential of the treated infection.

Artemisinin is eliminated by metabolic biotransformation, predominantly by CYP 2B6, to inactive metabolites. The artemisinins are weak inducers of some important drug-metabolizing enzymes and augment their own clearance (15, 16). After oral or parenteral administration, artemether, artemotil, and artesunate are all converted back rapidly to DHA in vivo, which is then eliminated by glucuronidation with an elimination half-life of ∼1 hour, both in healthy volunteers and in patients with malaria (Fig. 5). The broad stage specificity of action ensures that a single daily administration is sufficient for maximal killing of sensitive parasites. A 3-day artemisinin combination treatment (ACT) regimen provides antimalarial activity for two asexual parasite cycles and results in a reduction by a factor of about 100 million in parasite numbers within the infected patient—but this still leaves up to 100,000 parasites for the partner drug to remove, variably assisted by the immune response (14). The artemisinin component of the ACT therefore reduces the probability that a mutant resistant to the partner drug would arise from the primary infection, and, if effective, the partner should kill any artemisinin-resistant parasite that arose.

Artemisinins also have clinically important activity against other parasites. They kill the younger stages of trematodes and are effective in the treatment of schistosomiasis and fascioliasis and in animal models of Clonorchis infections (17, 18). Their in vitro activity against other protozoa is considerably less than against malaria parasites, although they might be of value in the treatment of African and South American trypanosomiasis (19). Artemisinins have anti-inflammatory properties and also inhibit angiogenesis and cell growth in several neoplastic cell lines, which suggests a potential role in cancer chemotherapy (20, 21).

## Artemisinin Combination Treatment

When artemisinins are given alone, 7-day regimens are required to maximize cure rates. Adherence with 7-day treatment courses is poor, so the combination partner in ACTs is usually a slowly eliminated antimalarial drug. This allows a complete treatment course to be given in 3 days (22). The first ACT to be evaluated systematically was artesunate-mefloquine (3, 23). This was deployed in 1994 on the northwest border of Thailand—an area of mefloquine-resistant falciparum malaria—and has retained efficacy over the subsequent 14 years (24). The first fixed-dose ACT (artemether-lumefantrine) followed soon afterward. Other ACTs have combined artesunate with existing drugs (sulfadoxine-pyrimethamine or amodiaquine) (6). Their evaluation (25) coincided with increasing realization that, whereas mortality from most infectious diseases (with the exception of HIV-AIDS) was declining, malaria mortality was rising (26, 27). This was attributed directly to the continued use of increasingly ineffective antimalarial drugs, mainly chloroquine and sulfadoxine-pyrimethamine (SP). Where the partner drug had not already fallen to resistance, the new ACTs were effective and well tolerated, but they were more expensive than the failing monotherapies.

View Abstract