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Is artemisinin monotherapy again allowed by WHO?

October 17, 2015 - 19:22 -- Irene Teis

The paper « Efficacy of a Novel Sublingual Spray Formulation of Artemether in African Children with Plasmodium falciparum Malaria » (Daryl Bendel et al.,Antimicrob. Agents Chemother. November 2015 vol. 59 no. 11 6930-6938) which was posted recently on www, raises this important question. The clinical trials were run by an Australian pharmaceutical company in Burkina Faso, Rwanda and Ghana

It is in conflict with the WHO position « WHO urges regulatory authorities in malaria-endemic countries to take measures to halt the production and marketing of these oral monotherapies, and promote access to quality-assured artemisinin-based combination therapies (ACTs). The continued use of oral artemisinin-based monotherapies is considered to be a major contributing factor to the development of resistance to artemisinin derivatives.

Furthermore artemether in this drug is delivered in a spray of 6% artemether in coconut oil. But many health organizations advise against the consumption of coconut oil due to its high levels of saturated fat, including the United States Food and Drug Administration, World Health Organization, Coconut oil contains a large proportion of lauric acid, a saturated fat that raises total blood cholesterol levels.


Submitted by Francois Nosten on

The ban on artemisinin mono-therapy by the WHO is only for the treatment of uncomplicated malaria, to reduce the risk of resistance. However the communication strategy of the WHO on this subject was not adequate. Artemisinin derivatives (in particular artesunate tablets) are still needed to treat specific cases such as uncomplicated hyper-parasitaemic patients and pregnant women. In meetings WHO indicated that it will ensure that artesunate tablets remain available in hospitals but in practice this was not done, and it is now almost impossible to procure them, putting our patients at risk. The very small amount of coconut oil in the artemether spray is unlikely to raise blood cholesterol.

Submitted by Irene Teis on

You imply that hundreds or thousands of children are dying of severe malaria because the prescriptions of WHO are inadequate. This would be criminal and immoral negligence.

Submitted by Francois Nosten (not verified) on

No, this is not what I am implying. Most children with severe malaria are in Africa. Many are still treated with IV quinine instead of IV artesunate but this is the responsibility of the national programs, not WHO. What I am saying is that in some particular cases, the unavailability of artesunate tablets poses difficulties for the clinicians. Patients with high parasite counts (>4% infected RBC) but with no signs of severity (as per WHO criteria) should receive artesunate tablets first, to bring the parasite load down and then an ACT. Pregnant women in areas of multi-drug resistance should received artesunate plus clindamycin for 7 days, as per WHO guidelines, but this is not possible without artesunate tablets. see also: Nosten, F., E. Ashley, R. McGready, and R. Price. "We Still Need Artesunate Monotherapy." BMJ 333, no. 7557 (2006): 45

Submitted by Pierre Lutgen on

Dr Fr Nosten is right. An increase of cholesterol due to the consumption of coconut oil might be worrisome for a well fed American, but of negligible concern for an African child dying from severe malaria. It remains that the addition of plant oils to artemisinin or Artemisia annua deserves more attention. We have several anecdotical reports claiming that the addition of fatty food enhances the properties of this therapy. In fact the first publication concerning clinical trials with artemisinin run by the Qinghaosu Antimalaria Coordinating Research Group comparing pure artemisinin with artemisinin in oil suspension find a shorter clearance time for the suspension and a drasticllay reduced recrudescence within 3 months (Chinese Medical Journal,1979, 12, 511-516) But the thorough effect of combining oils with artemisinin has never been studied and indiscrimentally adding adjuvants to artemisinin derivatives is questionable.

It is long known that incubation of erythrocytes with fatty acids leads to lipid changes in the cell membrane (BH Lubin et al., J Clin Investig 1972, 51, 338-344) and in the balance of saturated and unsaturated fats. Variations in the nature of the dietary fat resulted in changes in fatty acid composition of rat erythrocyte ( BL Walker et al., Exp Biol Med 1964, 115, 1099-1103). Moringa oleifera is antagonistic with most malaria treatments because of its high content in PABA-paraminobenzoic acid. Some lipids enhance the crystallization of the toxic heme generated by plasmodium into hemozoin. Especially fatty acids of the species C16 :0 to C18 :4 (T Mitamura et al.,Parastol Internat, 2000, 49, 219-229). Oleic acid for example is indispensable for the intraerythrocytic proliferation of Plasmodium falciparum. (F Mi-Ichi et al., Parasitology, 2007 12 1671-7). Polyunsaturated fats of the families C20-4 to C22-6 rather lead to reduced parasitemia (LM Kumaratilale et al., J Clin Invest 1992, 89, 961-967). The sublingual administration of artemether in so called « neutral » oil (D Bendel et al., AAC, 2015, 59) raises thus many questions.


Artemisinin derivatives not only lead to resistance, widespread in Africa now. But these chemical derivatives also lead to strong side effects at high doses. Haemolytic, hepatotoxic, cytotoxic, neurotoxic, cardiotoxic, genotoxic, ototoxic, embryotoxic, spleenotoxic effects have been described in on October 19 2013. A recent paper from Germany T Rolling et al., Malaria Journal2012, 11 :169) describes post-treatment haemolysis by intravenous artesunate for three patients with pararasitaemia. The effect appears 2-3 weeks after the treatment. Several other research teams have seen strong evidence for similar haemolytic anemia caused by IV artesunate :

- Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium (A R Kreeftmeijer-Vegter12,Malaria Journal, 11:102 doi:10.1186/1475-2875-11-102, 2012).

- Artemisin-based combination therapies and their introduction in Japan, (S Kano, (Infect Chemother 16 : 375-382, 2010).

- Severe malaria, artesunate and haemolysis, (Pietro Caramello, Journal of Antimicrobial Chemotherapy Volume 67, Issue 8 Pp. 2053-2054. 2012).

Artemisia annua is a true polytherapy which has given >95% cure rate for hundreds of patients which have been treated in clinical trials in some 10 African countries, with infusions or powdered leaves . In our opinion more specific clinical trials are warranted with Artemisia annua against severe and cerebral malaria.