The artemisinin-like antimalarial drugs are remarkable because of their high potency and low toxicity. The selectivity of these agents appears to be due to their "activation" by haem iron which is present in significant amounts only in red blood cells which are infected with malaria parasites. However, the precise mechanism(s) by which artemisinin kills malaria parasites remains speculative; while the reaction of artemisinin with haem has been shown to yield a variety of reactive products these have been formed in the presence of organic solvents and their relevance to the antimalarial action of artemisinin in man is therefore uncertain.
To date there is little evidence that the neurotoxic effects of artemisinin seen in experimental animals are a problem in man. Of greater concern is the possible development of malaria parasites resistant to these agents and steps are being taken to prevent or at least delay the emergence of resistant strains by recommending that, as far as possible, artemisinin derivatives are used in combination with another effective antimalarial (see chapters 14 and 15). Currently, there is interest in promoting the local cultivation and use of A. annua as a herbal antimalarial treatment but while this practice is very attractive it carries with it the risk that the development of resistant parasites may be encouraged especially if patients receive inadequate doses of artemisinin. Recrudescence is a problem even with therapeutic doses of artemisinin-like drugs and is likely to be related to the relatively short elimination half-lives of these compounds. The development of new derivatives with improved pharmacokinetic profiles such as sodium artelinate may help to overcome this problem. Much energy has been put into the synthesis of artemisinin derivatives and also into the preparation of simple analogues based on the trioxane and tetra-oxane ring sytems (see chapter 12).
It is also possible that other naturally occurring peroxides may prove to be lead compounds for novel antimalarial agents. Like A. annua, the Chinese herb yingzhao (Artabotrys unciatus) is used traditionally in China for malaria treatment and this species contains the terpenoid peroxides yingzhaosu A and C (Zhang et al., 1988). The synthetic antimalarial arteflene has been developed from yinghaosu A and has been evaluated for the treatment of falciparum malaria in Gabonese children (Radloff et al., 1996). Treatment with a single oral dose of 25 mg/kg was not effective in eradicating parasites and this was shown to be due to recrudescence rather than re-infection. More importantly, indications of both R2 and R3 resistance development were seen in parasites from 8 of the 20 patients treated. The development of arteflene as an antimalarial has now been discontinued due to the problem of recrudescence but other analogues are being investigated, (Posner, 1998) and it is to be hoped that the continued investigation of natural products will help to meet the current need for safe and effective antimalarial drugs.
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