Was artemisinin the wrong choice ; is arteannuin-B the better one?

 

A recent paper (Anti-Plasmodial Polyvalent Interactions in Artemisia annua L. Aqueous Extract – Possible Synergistic and Resistance Mechanisms J  J Suberu  et al., PLoS ONE, November 2013  8 |11) opens the way for new antimalarial therapies. It gives an answer to several questions which had not been addressed properly in the scientific literature.

The paper studied the additive, synergistic or antagonistic effect of several constituants of Artemisia annua. It confirms clearly that the aqueous extract of Artemisia annua is 3x as potent as pure artemisinin. This is in line with the recent findings published by P Weathers showing that Artemisia annua leaf powder can be up to 40X as efficient as pure artemisinine (M Elfawal et al., PloS ONE, 7-12, e52746)

Very important is their finding that arteannuin-B and artemisinin are highly synergistic against a chloroquine resistant strain of Plasmodium falciparum. Artenannuin-B is in fact the sole molecule giving this synergy with artemisinin in a large series including artemisinic acid, dihydroarteminic acid. Artemisinin in fact is antagonistic with these two molecules which are its precursors in the plant.

Along the same lines a recent study from Czechoslovakia ( Xiaoxin X. Zhu, P Kostecka E Kmonickova et al. Pharmacol Rep., 65, 2013, 410-420) compares in depth the activities of artemisin and its precursors in several key factors in angiogenesis i.e. prostaglandin PGE2, IL-1β, IL-6, TNF-α, NO. Table 1. of this paper is impressive.

The nitric oxide NO production is strongly inhibited by arteannuin-B. Artemisinic acid, dihydroartemisin, artemisinin remain ineffective, even at the highest dose.

The LPS-activated production of PGE2 is inhibited 4x more by arteannuin-B than by artemisinin or dihydroartemisin.

Arteannuin-B has a strong inhibitory effect on the pro-inflammatory interleukines IL-1β, IL-6, TNF-α. Artemisinin, DHA, artemisinic acid show none. By our own studies we know that artemisinin has pro-inflammatory and immunodepressive effects.

The same paper also finds that arteannuin-B has a higher cytotoxicity than artemisinic acid, DHA or artemisinin for peritoneal cells of rats.

In fact, two years before already, in 2011, Pr T Efferth had  found that the cytoxicity of arteannuin-B is 10x higher than that of artemisinin against 8 different cancer cells (Phytomedicine, 18, 2011, 959-969)

In a comparison of Artemisia annua plants from 5 different origins (PM de Magalhaes et al., Food Chemistry, 2012, 134-2, 864-71), arteannuin-B could also explain the strong  inhibitory effect against the pro-inflammarory IL-6 and IL-8 for the plant from Luxembourg which is very poor in artemisinin but rich in arteannuin-B.

The larvicidal activity for artemisinin, arteannuin-B and artemisinic acid in the extract of an Artemisia annua species from India is in the same range, but as the concentration of arteannuin-B in this plant is much higher it has probably the major larvicidal contribution (G Sharma et al., Parasitol Res 25, Oct 2013).

If really arteannuin-B offers more therapeutical potential than artemisinin one may wonder why this molecule already discovered and described in 1973 (D Jeremic, et al., Tedrahedron Letters 14-32, 3039-3042, 1973) and 1974 (DG Leppard et al., Helv Chim Acta, 57-3, 602-15, 1974) was subsequently neglected  versus artemisinin which was only discovered in 1978 and published in 1981 (Tu, Y.Y. et al The constituents of Artemisia annua L. in Yao Xue Xue Bao 16, 366370 , 1981).

All this could explain why the Artemisia annua tea from Luxembourg is very efficient against malaria, despite the fact that it contains only 0.1 % of artemisinin. But it contains 10 x more arteannuin-B. These concentrations are exactly the opposite for the hybrid propagated by pharmaceutical companies in Africa, i.e. very rich in artemisinin but with  undetectable contents of arteannuin-B.

The clinical trials we have run so far with infusions and capsules in several countries give cure rates > 95%. A very encouraging result was obtained  with 15 capsules of 1 gr each over 10 days. In total only 15 mg of artemisinin for a complete cure. We are far from the astronomical 1000 mg/day prescribed by WHO in ACTs (WHO/MAL/98/1086).

In none of the aformentioned trials resistance could be detected.

Pierre Lutgen

2 dec 2013


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