Abstract
Artemisinin, from which the artemether component of Coartem®(artemether/lumefantrine, AL) is derived, is obtained from the plant sweet wormwood (Artemisia annua) which has been used for over 2,000 years as a Chinese herbal remedy. Artemisinin was first identified by Chinese researchers as the active anti-malarial constituent of A. annua and its derivatives were found to be the most potent of all anti-malarial drugs. Artemether acts rapidly, reducing the infecting parasite biomass by approximately 10,000-fold per asexual life cycle. Lumefantrine, the other active constituent of AL, acts over a longer period to eliminate the residual 100-100,000 parasites that remain after artemether is cleared from the body and thus minimizes the risk of recrudescence. The two agents have different modes of action and act at different points in the parasite life cycle and show a synergistic action against Plasmodium falciparum in vitro. The combination of artemether and lumefantrine reduces the risk of resistance developing to either agent, and to date there are no reports of resistance to AL combined therapy in the malaria parasite that infects humans. Following a unique partnership agreement between Chinese authorities and Novartis, the manufacturer of AL, over 20 sponsored clinical studies have been undertaken in various malaria endemic regions and in travellers. These trials have involved more than 3,500 patients (including over 2,000 children), and led to identification of a six-dose, three-day regimen as the optimal dosing strategy for AL in uncomplicated falciparum malaria. AL has consistently shown 28-day polymerase chain (PCR)-corrected cure rates greater than 95% in the evaluable population, meeting WHO recommendations. More recently, Novartis and the Medicines for Malaria Venture have worked in partnership to develop Coartem® Dispersible, a new formulation designed specifically to meet the specific needs of children with malaria. The dispersible tablets have shown similar high response rates to those observed with crushed standard tablets of AL. A partnership agreement between Novartis and WHO has seen over 250 million AL (Coartem®) treatments (75% for children) being distributed to malaria patients in developing countries without profit, supported by training programmes and educational resources.
Highlights
Since it first received international licensing approval in 1999, Coartem® has become a mainstay of malaria treatment worldwide and is currently registered for use in almost 90 countries worldwide
Artemisinin is obtained from the Chinese herb sweet wormwood (Artemisia annua)
The first description of the use of sweet wormwood dates from the year 168 BC, when the plant was mentioned in a tomb of a member of the Han dynasty for the treatment of 52 diseases; in the year 1086 it was recommended in a Chinese compendium of medicines for the management of fevers and chills [2]
Summary
Since it first received international licensing approval in 1999, Coartem® (artemether/lumefantrine, AL) has become a mainstay of malaria treatment worldwide and is currently registered for use in almost 90 countries worldwide. Preclinical studies indicated that a 1:6 fixed combination of artemether and lumefantrine was well tolerated even at doses 10 times higher than those used in subsequent clinical trials [3], and based on the results from clinical trials in several hundred patients it was concluded that a 1:6 weight/ weight ratio was the optimum combination [3] These early studies showed that the AL combination was an effective and well-tolerated treatment for uncomplicated falciparum malaria [19,20,21,22]. Approximately 45 independent clinical trials have been published in the scientific literature These have each used a twice-daily regimen that maintained the blood concentration of artemether above the minimum effective concentration [1], to ensure that the infecting parasites are all exposed to high levels of artemether when they are in the middle third of their lifecycle – the point at which they are most susceptible to anti-malarial agents [23]. The risk of over-prescription of AL can, can be an issue with carer administration [34], and distribution through trained community health workers - if available - may help to ensure appropriate prescribing, especially if the community team is equipped with rapid diagnostic testing (See ‘Impact of large-scale deployment of artemether/ lumefantrine on the malaria disease burden in Africa: case studies of South Africa, Zambia and Ethiopia’ for more details [38].)
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