The Chinese in the mid-60’s made a concerted effort to find an effective antimalarial. Chinese scientists searched for effective antimalarials from both modern drugs and their ancient medicines. Project 523 was initiated on 23 of May 1967 for this purpose. It was a multicentre collaboration and led to the discovery of a new drug from the Chinese plant Artemisia annua . This plant has been used since ancient times for fever. Organic extracts of the leaves of Artemisia annua were thoroughly studied. Scientists gradually identified substances that had antimalarial properties, determined their chemical structures, and characterized their physico-chemical properties. Antimalarial properties of various chemical structures were tested in animal models of malaria and then in human malaria.
One great discovery, qinghaosu which was later called artemisinin, produced the most effective and the most rapid clearance of malaria parasites ever observed for any known drug. It was isolated in 1972 from the leaves of the traditional medicine Artemisia annuaand was found powerful against Plasmodium falciparum.
Experts in chemistry labored to alter the molecule of qinghaosu by chemical reduction to produce dihydroqinghaosu (dihydroartemisinin) and this semisynthetic drug was even a more potent antimalarial. More chemical modification were made to make it more oil soluble, yielding arteether and artemether and more water soluble, yielding artesunate and artelinic acid. Artemether and artesunate as stable analogues have become popularly used drugs. However it took numerous laboratory studies and clinical trials to reach this stage. Professor Li Guo Qiao, a professor of traditional Chinese medicine from Guangzhou led extensive clinical trials that revealed the effectiveness of these drugs in both uncomplicated and cerebral malaria. In 1979 the Qinghaosu Antimalaria Coordinating Research Group published in English the physicochemical properties, antimalarial activity, and clinical evaluation of artemisinin in the Chinese Medical Journal.
The 2015 Nobel Prize for Medicine or Physiology was awarded to William C. Campbell and Satoshi Ômura for their discovery of avermectins, and to Tu You You for her contribution to the discovery of artemisinin.
The biological activity of artemisinin and its derivatives is due to the reactivity of an endoperoxide bridge in their molecular structure. Artemisinin derivatives are fast drugs, cause rapid clearance of the malaria parasites from the blood and produce rapid recovery from malaria symptoms. Because the drugs are metabolized by liver enzymes and removed from the body fast, another drug must be used that has a slower onset of action and longer duration of action and will complete the clearance of remaining parasites such a hypnozoites in tissues after the first 48 hr, hence the use of artemisinin based combination therapies (ACTs). Artemisinin and its derivatives are generally not used in monotherapy.
Artesunate given orally in combination with another drug is used for uncomplicated malaria. However, intravenous artesunate (AS) and intramuscular artemether (AM) are clearly effective in reducing incidences of malaria deaths around the world.
Artesunate is a prodrug that is rapidly converted to its active form dihydroartemisinin (DHA) within the human body. Artesunate, because of its solubility can be formulated as oral, rectal, intramuscular, and intravenous pharmaceutical preparations making it useful for severe and complicated malaria where different routes of administration are needed. Artesunate injection is used for severe malaria in hospitalized patients. It is active against various malaria parasites including against P. ovale, P. malariae, and P. knowlesi.
Artesunate is on the World Health Organization’s List of Essential Medicines, which are considered effective and safe medicines needed in the health system.