A strange feature of plants from the Artemisia family is that they do not contain ascorbic acid (vitamin C)
Iron supplements and malaria
One of the first mistakes of Western medicine in Africa was the iron supplementation to the Somali nomads in 1968. Blood analysis of these nomads had shown that according to European standards they were suffering from anemia (MJ Murray et al., Brit Med J. Oct 1978, 1113-1116). But iron administration was associated with a significant increase of the disease it was supposed to suppress and even to reactivation of pre-existing diseases. The conclusion of the authors was that iron deficiency eventually plays a part in suppressing certain infections. Since that date it has been documented by many authors that anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Plasmodium falciparum infects iron-deficient erythrocytes less efficiently, but the mechanisms remain obscure (Clark MA1,et al., Commun. 2014 Jul 25;5:4446. doi: 10.1038/ncomms5446). Iron deficiency accelerates suicidal erythrocyte death,. Moreover iron deficiency impairs in vitro intraerythrocytic growth and infection of erythrocytes. In mice, iron-deficient erythrocytes are more rapidly cleared from circulating blood. Iron deficiency favourably influences the course of malaria, an effect partially due to accelerated suicidal death and subsequent clearance of infected erythrocytes (Koka S et al.,Biochem Biophys Res Commun. 2007, 357(3):608-14.)
Green tea, coffee are well known to reduce nonheme-iron absorption. Catechins, gallic acid, chlorogenic acid, rosmarinic acid, ellagitannins are the main chelating agents. Quercetin inhibits intestinal iron absorption (M Lesjak et al., PLOS one, 2014, 9, e102900). Its glucoside rutin present in most Artemisia species is even a stronger inhibitor. As iron supplements preferably accumulate in the liver where sporozoites need iron for their multiplication into thousands of merozoites, this is a critical control element. Quercetin as it is found in aqueous extracts of Artemisia also has very strong antihemolytic properties (A Naqinhezad et al., Eur Rev Med and Pharmacol Sc, 2012, 16, 88-94). Hemolysis is common in malaria and liberates extracellular hemoglobin which triggers specific pathophysiologies like inflammation, hepatic failure and anemia. Artemisia annua from Cameroon contains 4 times more rutin than Artemisia annua from Luxembourg. This might explain its stronger inhibition of beta-hematin. Luteolin, one of the main constituants in Artemisia afra, is also a strong chelator of iron, it reduces the absorption of free iron from food, inhibiting the Fenton reaction which generates OH radicals ( Ai-Hong-Yang et al., RSC Advances 48, 2014),. The action of polyphenol compounds on iron mediated antioxidant and prooxidant effects is complex (NR Perron, Dissertation, Clemson University 2008). They are related to the stability constants of one or more polyphenols binding to an iron ion in aqueous solution. For rutin and quercetin they were among the highest.
Vitamin C and malaria
The malaria belt of the world (tropical regions) with rich sources of vitamin C constitutes malaria endemic zones. In these zones, where vitamin C rich food such as citrus fruits and green vegatables abound, a mutual relationship between the two appears to exist. A database of vitamin C contents in tropical vegetables and foods has been published (M Ogunlesi et al., Int J Electrochem Sci 2010, 5, 105-115. Moringa oleifera for example contains 7 times more vitamin C than oranges.
Ascorbic acid affects malaria in several pathways.
- The enhancement of iron absorption by ascorbic acid is known since decades (L Hallberg et al., Int J Vitam Nutr Res Suppl 1989, 30, 103-8), (B Teucher Int J Vitam Nutr Res 2004,74, 403-19). Ascorbic acid is probably the most effective absorption enhancer of non-haem iron. This may be beneficial against anemia but is detrimental for malaria.
- ACTs are rendered less effective if taken with multivitamins that contain constituents such as vitamin C. Ascorbic acid has also been shown to inhibit the antiplasmodial activity of ellagic acid leading to a 4fold increase of IC50 for this tannin derivative. (P Soh PLOS one, 2013, 10). Ascorbic acid also reduces the antimalarial activity of several ketones (S Mahajan et al., Parasitology2005, 131, 459-466). A study from Nigera involving 80 malaria infected adult patients (OC Adamanya et al., Int J Pure Appl Sci Technol, 2012, 10, 5157) shows that co-administration of orange juice, grapefruit juice or vitamin C concomitant with artesunate or amodiaquine severely diminishes the efficacy and potency of these widely used antimalarial drugs. In most of the patients under concomitant administration parasitemia was not cleared at the end of the treatment as it was for the controls where only artesunate or amodiaquine were administered.
- Ascorbic acid may increase parasitemia. The uptake of ascorbic acid into erythrocytes is increased as a result of malaria infection (R Stocker et al., Biochim Phyys Acta 1986, 881, 391-7). Vitamin C particularly enhances the develpment of young parasites (E Marva et al., Trop J Med Parasitol 1992, 43 , 17-23). In an in vivo study the therapeutic potential of selected micronutients in Plasmodium berghei infected mice showed that vitamin A caused a caused a 41 % suppression of parasitemia on day 4, vitamin E 35%, zinc 42 %, selenium 81 %, chloroquine 100% and Vitamin C none (Ol Iribhoghe et al., Biol and Med 2012, 4, 193-201). In another in vivo trial Plasmodium yoelii infected mice received a supplement of vitamin C, but this did not reduce damages in both morphology and histology of liver and spleen. On days 7 to 11 parasitemia however increased by 30% (T Rungruang et al., Inter Food Res J, 2013, 20, 1639-1643). It appears that the Plasmodium parasite needs vitamin C. It has been noticed that in vitro cultures many parasite isolates see their population decline below 6 mg/L of ascorbic acid (CR Brockelman et al., Parasitol Res 1987 73, 107-12).
There are very few medicinal plants which do not have a documented antiplasmodial effect. This is the case however for Curcuma longa, Moringa oleifera and Pomegranate juice. A study in Thailand confirmed that extracts of the Curcuma plant had no suppressive effect in Plasmodium yoelii infected mice (Alkakarach Kettawan et al., Siriaj Med J 2012, 64, 78-81). Pomegranate juice, curcuma and moringa powder have very all a very high antioxidant power. Pomegranate juice for example is 2-3 times stronger than red wine or tea (MI Gil et al., J Agric Food Chem, 2000, 48, 4581-89). Curcuma longa 50 times higher than tomato or garlic. Moringa oleifera 3 times higher than spinach or peas (Vuzumsi Pakade et al., South Afr J Sci. 2013, 100, 3/4), All these extracts are very rich in polyphenols and flavonoids. It was often assumed that a high polyphenol content and/or high antioxidant power were leading to good antimalarial properties. But this claim does not hold in light of a study from Thailand (Siriporn Tuntipopipat et al., The Journal of Nutrition, 2006, 136, 2970-2974). Despite the much higher amount of phenolics in Curcuma longa than in another plant, the latter has excellent antimalarial properties and the turmeric containing food none. The authors conclude that not only phenol quantity plays a role but also their quality, and particularly the iron binding capacity. Moringa oleifera and Curcuma longa are very rich in iron and ascorbic acid. Moringa for example contains 7 times more vitamin C than orange juice and 3 times more iron than roast beef. A deadly mix in case of malaria infection.
For several of these reasons, ascorbic acid supplement will act as booster to malaria parasites in carriers. But it is difficult to find this warning in WHO documents or in prescription information about artemether, amodiaquine, mefloquine, lumefantrine. In a survey run in Nigeria in health centers, 200 questionnaires were returned showing that 173 (86.5%) of the medical staff were not aware that taking antioxidants such as vitamin C concurrently with ACTs caused an inhibition of the antimalarial effect. (MK Omole et al., Niger J Pharmaceut Res. 2010, 8, 84-91).
Who is to blame ? Entering the keyword artemisinin on PubMed gives 5696 research papers. None of them refers to a possible antagonism with vitamin C ? Cui bono ? World production of synthesized vitamin C is currently estimated at 110,000 tonnes annually.