## 1 Introduction
### Artemisinin (Qinghaosu)  
As has been noted, after a brief respite lasting only a few decades, malaria was once again on the increase in the 1960s. In 1967, the Chinese government launched a program to discover new antimalarial drugs based on a systematic investigation of indigenous plants used in TCM. When the Chinese scientists made infusions of _A. annua_ with hot or boiling water, as described in the ancient texts, they observed no activity against mice infected with _Plasmodium berghei_ (a rodent malarial parasite). However, thanks to the insight of Prof. Tu, cold ethereal extracts of _A. annua_ were also tested and these did show encouraging activity, leading to the isolation of the active principle, artemisinin, in 1972 (the original reports of this new drug referred to \"Qinghaosu\", meaning \"principle from Qinghao\" [4]). Nowadays, artemisinin is extracted from _A. annua_ using diethyl ether, hexane, petroleum ether or even petrol as solvent [5]. At first sight, the lack of effectiveness for hot water extracts from _A. annua_ appears to be at variance with the reports in the traditional pharmacopeias (in addition, we now know that artemisinin is virtually insoluble in water). One possible explanation is that the original recipes normally required that _A. annua_ preparations be made in conjunction with other herbs (so-called \"minister\" or \"guide\" herbs). For example, in the herbal \"Wen Bing Tiao Bian\" (1798), an infusion of _A. annua_ together with _Amyda sinensis_, _Rehmannia glutinosa_, _Anemarrhena asphodeloides_ and _Paeonia suffructicosa_ is described. It is quite possible that saponins, or other components from the latter three herbs which are capable of acting as detergents, might be able to assist the dissolution of artemisinin in water (_cf._ the suggestion in Section 2.4 that flavonoids, which are present both in _A. annua_ and other herbs, may be able to potentiate the antimalarial effect of artemisinin in crude plant preparations). Clinical studies in the late 1970s with patients infected with _P. vivax_ or _P. falciparum_ demonstrated that artemisinin could kill the malarial parasite very quickly at the schizont stage of the parasite's life cycle (_i.e._ while it infected the human red blood cell) and with no obvious side effects [6]. Most importantly, artemisinin was completely effective in the treatment of chloroquine-resistant _Falciparum_ malaria [7]. The discovery of this new and potent antimalarial attracted the attention of the World Health Organization (WHO), which had the resources to develop artemisinin globally; and both _A. annua_ and artemisinin soon became well known outside of China. However, the therapeutic value of artemisinin was limited by its low solubility in both oil and water, and this has lead to the development of semi-synthetic drugs with pharmacological properties superior to those of the parent [8]. The most important such derivatives are artemether, arteether and artesunate (Figure 1), which exhibit greater potency than artemisinin itself, as well as improved solubility, and favourable metabolic and hydrolytic stabilities. Formulations based on these drugs are now at the heart of the WHO's global fight against malaria The entire world production of such semi-synthetic artemisinin derivatives is currently reliant on harvesting and extraction of artemisinin from _A. annua_ plants, which is practiced on a multi-tonne scale in countries such as China and Vietnam. Malaria is now the most serious infectious disease in the World, with at least 300 million cases reported every year. It is estimated to be responsible for up to 2 million deaths annually - mainly amongst children - with more than half of the deaths occurring amongst the poorest 20% of the World's population.