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

December 2, 2013 - 20:55 -- Pierre Lutgen


A recent paper (Suberu JO, Gorka AP, Jacobs L, Roepe PD, Sullivan N, Anti-Plasmodial Polyvalent Interactions in Artemisia annua L. Aqueous Extract – Possible Synergistic and Resistance Mechanisms. PLOS 2013 doi/10.1371/annotation/57ae25b0-d2c8-444b-ab62-f047c5f3e01e) opens the way for new antimalarial therapies. It provides answers to several questions that have not been addressed properly in the scientific literature.The paper studied the additive, synergistic or antagonistic effect of several constituents of Artemisia annua. It confirms clearly that the aqueous extract of Artemisia annua is three times 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 artemisinin(Mostafa A. Elfawal, Melissa J. Towler, Nicholas G. Reich, Douglas Golenbock, Pamela J. Weathers, Stephen M. Rich , Dried Whole Plant Artemisia annua as an Antimalarial Therapy. PLOSOne: December 20, 2012

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 that has a synergetic reaction 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  (XX Zhu, Lan Yang,Yujie J. Li,Petra Kostecká, Eva Kmoníčková, Zdeněk Zídek Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis. Pharmacol Rep, Volume 2013; 65(2): 410–420. see Table 1 of this paper).compares in depth the activities of artemisinin 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, and artemisinin remain ineffective, even at the highest dose. Arteannuin-B inhibits the LPS-activated production of PGE2 four times more than artemisinin or dihydroartemisin, and it 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  (personal communication Dr M Dicato, Luxembourg 2009). 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, already two years ago, in 2011, Prof T Efferth found that the cytoxicity of arteannuin-B is ten times higher than that of artemisinin against 8 different cancer cells(Thomas Efferth, Florian Herrmann, Ahmed Tahrani,,Michael Wink. Cytotoxic activity of secondary metabolites derived from Artemisia annua L. towards cancer cells in comparison to its designated active constituent artemisinin,Phytomedicine. Volume 18, Issue 11, 15 August 2011, Pages 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.

In a study on the antiulcerogic activity of sesquiterpene lactones from Artemisia annua it was found that only deoxyartemisinin and arteannuin-B decreased the ulcerative lesion index, artemisinin did not (MA Foglio et al., Planta Medica 2002, 68, 515-18).

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).

Against cytomegalovirus arteannuin-B displayed stronger activity than dihydroartemisinin, artemisinin none!(Flobinus A1, Taudon N, Desbordes M, Labrosse B, Simon F, Mazeron MC, Schnepf N.Stability and antiviral activity against human cytomegalovirus of artemisinin derivatives. J Antimicrob Chemother. 2014 Jan;69(1):34-40. doi: 10.1093/jac/dkt346). A strange finding also from Brazil. Deoxyartemisinin decreased the ulcerative lesion index produced by ethanol and indomethacin in rats, and artemisinin not. Another strange finding from Brazil is that artemisinic acid is effective against Schisostoma Manzoni and artemisinin not. (SM Allegretti, C Nascimento, The Use of Brazilian Medicinal.Plants to Combat SchistosomaMansoni, Universidade Campinas, Brazil 2012 DOI: 10.5772/27399)

If arteannuin-B really offers more therapeutic potential than artemisinin, one may wonder why this molecule, already discovered and described in 1973 and 1974

(D.Jeremić, A. Jokić, A. Behbud, M. Stefanović A new type of sesqiterpene lactone isolated from artemisia annua L. arteannuin B, Tedrahedron Letters 1973 vol14- Iss 32, 3039-3042),   (Uskoković MR, Williams TH, Blount JF. The structure and absolute configuration of arteannuin B. Helvetica chimica acta 57:3 1974 Apr 27 pg 600-2)

was subsequently neglected in favour of artemisinin, which was only discovered in 1977 and the first peer reviewed papers of the Chinese team with the name of Tu Youyou and relating the discovery of artemisinin was published in 1979 by a team of Chinese scientist. Tu youyou was not the main author but co-author. (Liu JMNi MYFan JFTu YYWu ZHWu YLChou WS (1979Structure and reaction of ArteannuinActa Chim Sin 37:129143)

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 ten times 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 aforementioned trials resistance could be detected.



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