Invited review
Artemisinin: mechanisms of action, resistance and toxicity

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Abstract

Artemisinin and its derivatives are widely used throughout the world. The mechanism of action of these compounds appears to involve the heme-mediated decomposition of the endoperoxide bridge to produce carbon-centred free radicals. The involvement of heme explains why the drugs are selectively toxic to malaria parasites. The resulting carbon-centred free radicals are alkylate heme and proteins, one of which is the translationally controlled tumour protein. Clinically relevant artemisinin resistance has not been demonstrated, but it is likely to occur since artemisinin resistance has been obtained in laboratory models. At high doses, artemisinin can be neurotoxic but toxicity has not been found in clinical studies. The mechanism of neurotoxicity may be similar to the mechanism of action.

Introduction

Artemisinin and its derivatives represent a very important new class of antimalarials; they are becoming more and more commonly used throughout the world. The most important artemisinin derivatives are artesunate, artemether, arteether and dihydroartemisinin. Newer semisynthetic and synthetic derivatives are also being developed. The artemisinin derivatives act quickly and are eliminated quickly. Their rapid onset makes them especially effective against severe malaria. Their rapid disappearance may be a key reason why artemisinin resistance has been so slow to develop, and may also explain why recrudescences (treatment failures) are so common when these drugs are used in monotherapy.

Artemisinin was developed from an ancient Chinese herbal remedy. Artemisia annua – sweet wormwood or ‘qinghao’ – was used by Chinese herbal medicine practitioners for at least 2000 years. In 1596, Li Shizhen, a famous herbalist, recommended that patients with fever “take a handful of sweet wormwood, soak it in a sheng (∼1 l) of water, squeeze out the juice and drink it all.”. In 1967, Chinese scientists screened a series of traditional remedies for drug activities, and found that extracts of qinghao had potent antimalarial activity. In 1972, the active ingredient was purified and first named qinghaosu (essence of qinghao), and then later renamed artemisinin. Chinese scientists tested qinghaosu and its derivatives on thousands of patients and published the results of these studies in the late 1970s and early 1980s (for a review of the history of artemisinin, see Meshnick, 1998, Meshnick and Dobson, 2001).

Artemisinin derivatives were used widely in China by the 1980s. Western interest in these agents began to grow as multidrug resistant Plasmodium falciparum strains began to spread, especially in Southeast Asia. By the early 1990s, artemisinin derivatives were being widely used in Thailand, Burma and Vietnam. Several artemisinin derivatives are now being developed by Western pharmaceutical companies. The results of all clinical studies using artemisinin derivatives to treat both complicated and uncomplicated malaria have been compiled into two reviews in the Cochrane Library (McIntosh, 1999a, McIntosh and Olliaro., 1999b).

Section snippets

Mode of action

Artemisinin's structure is unlike those of any other known antimalarial and is thus likely to have a different mechanism of action. The first clue to its mechanism came from synthetic chemists who demonstrated that the endoperoxide bridge was necessary for antimalarial activity (Antimalarials, 1972, Brossi et al., 1988). Since peroxides are a known source of reactive oxygen species such as hydroxyl radicals and superoxide (Halliwell and Gutteridge, 1999), this observation suggested that free

Resistance

There is currently no evidence for clinically relevant artemisinin resistance. However, since artemisinin derivatives are being widely used, artemisinin resistance is likely to develop eventually. Artemisinin-resistant strains of P. falciparum (Inselburg, 1985) and Plasmodium yoelii (Peters and Robinson, 1999) have been obtained in the laboratory. Various clinical isolates and lab strains of P. falciparum have been found to vary in sensitivities to artemisinin in vitro (reviewed in Le Bras, 1998

Toxicity

Adverse effects are rare in patients treated with artemisinin derivatives. In a prospective study of over 3,500 patients in Thailand, there was no evidence for serious adverse effects (Price et al., 1999a). Artemisinin derivatives also appear to be safe for pregnant women (McGready et al., 1998).

In several animal studies however, artemisinin derivatives have been clearly shown to cause neurotoxicity at high doses (reviewed in Brewer et al., 1998; see also Nontprasert et al., 1998, Nontprasert

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