Artemisinin Toxicity

Meshnick SR. (2002) Artemisinin Mechanisms of action, resistance and toxicity. Int J Parasitol 32 1655-1660. 

Nontprasert A, Pukrittayakamee S, Dondorp AM, Clemens R, Looareesuwan S, White NJ. (2002) Neuropathologic toxicity of artemisinin derivatives in a mouse model. Am J Trop Med Hyg 67 423 29. 

The previous section dealt with the mechanisms behind the bioactivation of 1,2,4-trioxanes and endoperoxides. In this section we will examine briefly the suggested targets of the artemisinins. Since the original proposal by Meshnick and coworkers it is still believed by many researchers in the field that heme liberated from the haemoglobin proteolysis process is the species responsible for the bioactivation of the endoperoxide bridge to potentially toxic free radicals in the food vacuole of the parasite (see above). 

Clark R et al (2008) Developmental toxicity of artesimate in the rat comparison to other artemisinins, comparison of embryotoxicity and kinetics by oral and intravenous routes, and relationship to maternal reticulocyte count. Birth Defects Res B Dev Reprod Toxicol 83 397-406... 

Artemisia annua L. A. apiacea Hance ex Walpers Qing Guo (Stinking artemisia) (aerial part) Dihydroartemisinin, artesunate, artemisinin, chloroquine, flavonoids, sesquiterpene.33-269-476 This herb is mildly toxic. A schizonticidal agent, antimalarial, treat infections of multidrug-resistant strains of Plasmodium falciparum, the cause of human malignant cerebral malaria. 

Artemisia annua L. China Dihydroartemisinin, artesunate, artemisinin, chloroquine.33 This herb is mildly toxic. A schizonticidal agent, antimalarial. 

Clearly, extensive whole-animal toxicity studies have not been warranted in the development of structure-toxicity relationships. Accordingly, Wesche et al.11 and Edwards and colleagues12,13 have developed in vitro methods for assessing neurotoxicity in neuronal cells. Based on these studies, dihydroartemisinin has been found to be the most neurotoxic artemisinin analog (Figure 9.2). 

The peroxide group is essential for neurotoxicity, and, depending on the assay, artemisinin could be considered relatively nontoxic or quite toxic. Removal of the oxygen atom at C-10 (10-deoxoartemisinin) resulted in a marked reduction in neurotoxicity. 

Fishwick, J. and Edwards, G. The toxicity of artemisinin and related compounds on neuronal and glial cells in culture, Chem. Biol. Interact., 96, 263, 1995. 

Artemisinin compounds clear parasites from the blood more rapidly than any other antimalarial agent, by a unique pharmacodynamic action. They are concentrated in parasitized erythrocytes, and structure-activity relations (see Chapter 2) suggest that their endoperoxide bridge is essential for the antimalarial effect. A critical step in the mechanism of action seems to be a hemin-catalyzed reduction of the peroxide moiety, which results in free radicals and reactive aldehydes that subsequently kill the malaria parasites. The hemin-rich internal environment of the parasites is assumed to be responsible for the selective toxicity of artemisinin toward these organisms. 

Thousands of patients in China and Myanmar (formerly Burma) have been successfully treated but, as of 1990, artemisinin is unavailable elsewhere. Relatively low toxicity has been observed, along with substantial effectiveness. Unfortunately, the relapse rate is high. Nevertheless, use of artemisinin or its derivatives in conjunction with other treatments is considered promising [67],... 

Figure 5.1 Examples of terpenoids that are of commercial importance or whose functional role in plants has recently been investigated. Isoprene may stabilize membranes at high temperatures. Camphor, artemisinin and paclitaxel (taxol) are valuable pharmaceuticals. The other three compounds appear to be involved in plant defence pulegone is toxic to herbivores polygodial is a herbivore feeding deterrent and (3 )-4,8-dimethyl-1,3,7-nonatriene, a Cn homoterpene, functions to attract herbivore enemies to herbivore-damaged plants.

Qinghao (Sweet Wormwood) is the dried aerial parts of the herb Artemisia annua L. (Asteraceae family), which has been used in China for centuries to treat fever and malaria. Artemisinin (Nl) (Qing Hao Su) (128), the active principle, directly kills Plasmodium falciparum (malaria parasites) with little toxicity to animals and humans. Thus, it is a clinically effective, safe, and rapid antimalarial agent (129, 130). The novel endo-peroxide link is essential for the antimalarial activity. 

All three Artemisia derivatives are quickly hydrolysed to the active substance dihydroartemisinin. They produce a more rapid clinical and parasitological response than other antimalarial drugs. There are no reports of significant toxicity, and as late as 1994 there was no convincing evidence of specific resistance, but chloroquine-resistant Plasmodium berghei is resistant to artemisinin as well. The recrudescence rate is fairly high (1). 

Drug activation by iron and heme may explain why endoperoxides are selectively toxic to malaria parasites. The malaria parasites live in a milieu of heme iron, which the parasite converts into insoluble hemozoin. Chloroquine, which binds heme, antagonizes the antimalarial activity of artemisinin. 

A large trial of the first fixed-dose combination of an artemisinin derivative likely to be licensed (artemether + benflumetol) had disappointing relapse rates compared with mefloquine monotherapy (6). In the 126 patients who took artemether + benflumetol there were no adverse effects attributed to drug treatment. However, less than 70% of patients were cured at 28 days. Benflumetol may be more effective at higher concentrations (12) but toxicity studies are lacking. 

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