Invited reviewArtemisinin: mechanisms of action, resistance and toxicity
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
References (95)
- et al.
Artemisinin enhances heme-catalysed oxidation of lipid membranes
Free Radic. Biol. Med.
(1997) - et al.
The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin
J. Biol. Chem.
(1998) - et al.
The Plasmodium falciparum translationally controlled tumor protein: subcellular localization and calcium binding
Eur. J. Cell Biol.
(1999) - et al.
The toxicity of artemisinin and related compounds on neuronal and glial cells in culture
Chem. Biol. Interact.
(1995) - et al.
The interaction of artemisinin with malarial hemozoin
Mol. Biochem. Parasitol.
(1994) - et al.
Ferryl-oxo heme intermediate in the antimalarial mode of action of artemisinin
FEBS Lett.
(2000) - et al.
The antimalarial action on Plasmodium falciparum of qinghaosu and artesunate in combination with agents which modulate oxidant stress
Trans. R. Soc. Trop. Med. Hyg.
(1987) - et al.
Qinghaosu, dietary vitamin E, selenium, and cod-liver oil: effect on the susceptibility of mice to the malarial parasite Plasmodium yoelii
Am. J. Clin. Nutr.
(1989) - et al.
Two patients with falciparum malaria and poor in vivo responses to artesunate
Trans. R. Soc. Trop. Med. Hyg.
(1998) - et al.
Artemisinin derivatives in the treatment of falciparum malaria in pregnancy
Trans. R. Soc. Trop. Med. Hyg.
(1998)
Artemisinin (qinghaosu): the role of intracellular hemin in its mechanism of antimalarial action
Mol. Biochem. Parasitol.
Effects of artesunate–mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study
Lancet
The biomimetic iron-mediated degradation of Arteflene (Ro-42-1611), an endoperoxide antimalarial – implications for the mechanism of antimalarial activity
Tetrahedron Lett.
Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite
J. Biol. Chem.
Effects of artemisinin derivatives on malaria transmissibility
Lancet
Hemoglobin catabolism and iron utilization by malaria parasites
Mol. Biochem. Parasitol.
Thalassaemia trait, red blood cell age and oxidant stress: effects on Plasmodium falciparum growth and sensitivity to artemisinin
Trans. R. Soc. Trop. Med. Hyg.
Molecular modeling studies of the artemisinin (qinghaosu)–hemin interaction: docking between the antimalarial agent and its putative receptor
J. Mol. Graph.
In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs
Int. J. Parasitol.
Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria
Exp. Parasitol.
The potential of artemether for the control of schistosomiasis
Int. J. Parasitol.
Artemether–lumefantrine for the treatment of multidrug-resistant falciparum malaria
Trans. R. Soc. Trop. Med. Hyg.
In vitro susceptibility of Plasmodium falciparum isolates in Vietnam to artemisinin derivatives and other antimalarials
Acta Trop.
Hemin-catalyzed decomposition of artemisinin (qinghaosu)
Biochem. Pharmacol.
Reaction between ferriprotoporphyrin IX and the antimalarial endoperoxide artesunate gives an intermediate species with enhanced redox catalytic activity
J. Pharm. Pharmacol.
Chemical studies on qinghaosu (artemisinine)
J. Tradit. Chin. Med.
Effects of antimalarials and protease inhibitors on plasmodial hemozoin production
Mol. Biochem. Parasitol.
Reaction of antimalarial endoperoxides with specific parasite proteins
Antimicrob. Agents Chemother.
Structure–activity relationships of the antimalarial agent artemisinin 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies
J. Med. Chem.
Synthesis and reactions of antimalarial bicyclic peroxides
J. Heterocycl. Chem.
In vitro and in vivo potentiation of artemisinin and synthetic endoperoxide antimalarial drugs by metalloporphyrins [In Process Citation]
Antimicrob. Agents Chemother.
Artemisinin mediated alteration of haemin to a delta-meso oxidation product: relevance to mechanism of action
J. Chem. Soc. Perkin Trans.
Immunoprecipitation of [(3)H]dihydroartemisinin translationally controlled tumor protein (TCTP) adducts from Plasmodium falciparum-infected erythrocytes by using anti-TCTP antibodies
Antimicrob. Agents Chemother.
Factors relating to neurotoxicity of artemisinin antimalarial drugs ‘listening to arteether’
Med. Trop. (Mars)
Arteether, a new antimalarial drug: synthesis and antimalarial properties
J. Med. Chem.
EPR evidence for the involvement of free radicals in the iron-catalysed decomposition of qinghaosu (artemisinin) and some derivatives; antimalarial action of some polycyclic endoperoxides
Free Radic. Res.
Alkylating capacity and reaction products of antimalarial trioxanes after activation by a heme model
J. Org. Chem.
The infectivity of gametocytes of Plasmodium falciparum from patients treated with artemisinin
Chin. Med. J. (Engl.)
The mechanisms of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria
J. Infect. Dis.
Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum
Mol. Pharmacol.
Neurotoxicity and artemisinin compounds do the observations in animals justify limitation of clinical use?
Med. Trop. (Mars)
Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum
Mol. Microbiol.
Artemisinin (qinghaosu) – a new gametocytocidal drug for malaria
Chemotherapy
The chemotherapy of rodent malaria
Ann. Trop. Med. Parasitol.
Morphological and immunocytochemical effects of dihydroartemisinin on differentiating NB2a neuroblastoma cells
Neurotoxicology
Stage specific actions of antimalarial drugs on Plasmodium falciparum in culture
Am. J. Trop. Med. Hyg.
Probable resistance to parenteral artemether in Plasmodium falciparum: case reports from Mumbai (Bombay), India
Ann. Trop. Med. Parasitol.
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