Does artesunate promote malaria transmission?

The amino acid arginine is the only molecule in our food known to generate nitric oxide NO via NOS enzymes. It plays a key role in malaria therapy and cerebral malaria as described in previous blogs on http://www.malariaworld.org. NO derived from arginine is not only lethal for merozoites but also for gametocytes. NO is efficient against other diseases like leishmaniasis or filariasis (R O’Connor et al., Infection and Immunity, 2000, 68, 6101-6107).

The inducible nitric oxide synthase (iNOS) is NF-kB-regulated. Many botanical medicinal herbs and drugs derived from these herbs have been shown to have effects on the NO signaling pathway.

Polysaccharides may enhance this production, through a potent macrophage/monocyte activation. This has been demonstrated for acidic polysaccharides from Artemisia tripartita (Gang Xie et al., Photochemistry, 2008, 69, 1359-71), from Tanacetum vulgare (Gang Xie et al., Int Immunopharmacol 2007, 7, 1639-50), from mushrooms (JJ Volman et al., Mol Nutr Food Res, 2010, 54, 268-76). Also for Ginseng saponins and polysaccharides through the activation of NF-kB in macrophages (JY Kim et al., Biosc Biotechnol Biochem. 2005, 69, 891-895). But the polysaccharide with the strongest stimulation of NO synthesis is inulin (HN Koo et al, J Nutr Biochem, 2003, 14, 598-605).) The activation of NF-kB by inulin plays a key role (F Bahmani et al., J Am Coll Nutr, 2015 2, 1-8) and may explain the antimicrobial and tumoricidal activity. This explains why current research is directed to develop inulin as an adjuvant for influenza vaccines, hepatitis B vaccines, malaria vaccines and anti-tumour drugs (D Silva et al., Immunol Cell Biology 2004, 82, 611-16).

On the opposite, vitamins, particularly vitamin E and C inhibit iNOS and are detrimental for this reason during a malaria infection (see « Vitamin C and Malaria : beware ! » on http://www.malariaworld.org Mar 15 2015).

Coumarins, particularly scopoletin, strongly inhibit iNOS (Tien-Ning Chang et al., Evidence Based Complement Alternat Med, 2012, 595603). Its action to this effect is as strong as that of vitamin C (Xiujuan Yao et al., Int Immunopharmac. 2012, 14, 434-462). Quercetin is a NO inhibitor too, but scopoletin is ten times stronger (Aneta Janecki, Thesis, 2012, Universität Berlin). It needs to be mentionned at this stage that all genotypes of Artemisia annua are poor in quercetin (Laboratory Celabor, personal communication). Scopoletin is well present in most species of the Artemisia family. The NO inhibitory effect by scopoletin was demonstrated in Artemisia feddei (TH Kang et al., Planta Med 1999, 65, 400-3). It was even patented for Artemisia annua (US 6337095, 2002). The authors find higher concentrations of scopoletin in the stems than in the leaves (0.3 vs 0.2%). Very important in this context appears the fact that Artemisia annua from Luxembourg genotype only contains 0.02 % of scopoletin versus 0.2 % for Artemisia annua of the high artemisinin hybrid (Rosine Chougouo, Thesis, Université des Montagnes, Cameroon, 2011) and (Laboratory Celabor, personal communication). This to some extent may explain its excellent performance in clinical trials.

But sesquiterpene lactones even appear to be stronger NO inhibitors. This was first evidenced in 1997 for Artemisia ludoviciana in Mexico (P Bork et al., FEBS letters, 1997, 402, 85-90). The sesquiterpene lactones parthenolide and isohelenin prevented NF-kB activation completely as low as 5 microM. A similar effect was confirmed for the sesquiterpene lactone helenalin (G Lyss et al., J Biol Chem. 1998, 273, 33508-16). Ergolide, a sesquiterpene lactone from Inula britannica inhibits iNOS in macrophages (Jeung Whan Han et al., Brit J Pharmacol 2001. 133, 503-12). A similar effect for artemisinin was found in Italy (E Aldieri et al., FEBS letters, 2003, 552, 141-144). A more extensive study on 5 artemisin derivatives at the University of Heidelberg showed that among the five in a mouse macrophage model artesunate revealed the highest ability to inhibit generation of NO (J.Badireenath et al., Nitric Oxide, 2008, 19, 184-191).

In our own research we had found that in vitro pure artemisinin pretreatment strongly inhibited NF-kB activation (Dr Mario Dicato, personal communication 2008). We have performed extensive chemical analysis of the Artemisia annua produced at Luxembourg in comparison with the Mediplant hybrid variety. In all laboratories (Laboratoire National de la Santé in Luxembourg, Celabor in Belgium) we confirmed that Artemisia annua from Luxembourg is poor in artemisinin (0.1%) and scopoletin (0,02%) compared with 1.2% artemisinin and 0.2 % scopoletin in the hybrid. In the froth test the Artemisia from Luxembourg is also much richer in saponin than the Artemisia hybrid from Cameroon. We have confirmed that the Luxembourg genotype has better anti-inflammatory properties i.e.lower IL-6 and IL-8 activation PM de Magalhaes et al., Food Chemistry, 2012, 134, 864-71). In all clinical trials we have run in several African countries with infusion or capsules with Artemisia annua from Luxembourg the cure rate was >95%. In the literature we find two clinical trials with the Anamed high artemisin herb. In both cases the cure rate is much lower, around 75% and the recrudescence is high (CH Blanke, G Naisabhaet al., Tropical Doctor, 208, 38 . 113.6)(MS Müller et al., Trans R Soc Trop Med Hyg 2004, 98, 318-21)

We are currently running clinical trials to study the effect of different Artemisia species on gametocytogenesis.
Besides the inhibition of NO which leeds to the proliferation of gametocytes, artemisinin derivatives are strong immunosuppressors (AF Tawfik et al., Int J Immunopharmacol. 1990, 12 385-389) opening a wide angle door for recrudescence and reinfection.

The result of greed and stubborness : a Pyrrhic victory for Bigpharma and WHO, but a genocide looming for Africa.
Pierre Lutgen
3 december 2015

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