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Potassium in Artemisia plants, a key factor in malaria control?

October 14, 2014 - 06:54 -- Pierre Lutgen



Constant Tchandema and Pierre Lutgen

Potassium, the most abundant cation in the human body, regulates intracellular enzyme function and neuromuscular tissue excitability. Serum potassium is normally maintained within thenarrow range of 3.5 to 5.5 mEq/L.

Hypokalemia (plasma potassium concentrations below normal range) has been recognized over recent years to be very frequent in malaria and not only in severe malaria. In a study of 1415 patients in Thailand 44% of the patients infected by Plasmodium falciparum and Plasmodium vivax were hypokalemic (V Thanachartwet et al., Trop Doct 2008, 38, 155-157)

Similar percentages were found in India (H Jasmin et al., J Clin Diagnostic Res, 2012, 6 678-681). And in Nigeria (J Ebele et al., Int J Trop Med, 2010, 5, 46-49). And in Kenya (K Maitland et al., Pediatric Crit Care Med, 2004 Jan 5, 81-85). Potassium deperdition is enhanced by vomiting and diarrhoea.

From the existing literature, it is clear that hypokalemia is now a well documented phenomena in malaria patients and may have been highly underestimated. It also has been noticed in chikungunya (Rampal et al., J Assoc Physicians India, 2012, 56:598) and in dengue ( S Jha et al., Neurol India, 2010 58, 592-594) often leading to hypokalemic paralysis.

During malaria infection the cytosol of infected erythrocytes is poor in potasium and rich in sodium while in the parasite this relation is inversed (H Ginsberg et al., Z Parisitenk, 1986, 72, 185-199). The parasite plasma membrane potential changes with extracellular potassium concentration : it depolarizes at higher concentrations and hyperpolarizes a low concentrations (R Allen et al., J Biol Chem, 2004, 279, 11264-11272). In a medium with high potassium concentration the invasion of erythrocytes by merozoites is inhibited (W Trager et al., J Protozool 1984, 31, 562-7). Dietary potassium also reduces hypertension and acts as antioxidant by reducing ROS production (K Ando et al, Curr Vasc Pharmacol. 2010 8, 59-63)

More disturbing is the fact that artemisinin and its derivatives can potentially cause hypokalemia. They have been known to affect voltage-gated potassium currents, and their administration in patients of hypokalemia has been known to prolong the QT-interval. (Hara et al.J Vet Med Sci 69 697-702, 2007). Artemether significantly increases the potassium concentration in urine (R Akomalofe et al., Afric J of Biotechnology, 2011, 10, 4226-4233). The same diuretic effect has been noticed for artesunate (Indian J Pharmacol 2011, 43, 472-473). In fact the severe diuretic effect of intravenous injection of artesunate  is known since 2002 ( A Seguro et al., Am J Trop Med Hyg, 67, 2002, 473-4749). The use of artesunate recommended by WHO for intravenous injections is thus a double-edged weapon : the increased urinary loss of water and electrolytes can worsen renal failure.

Low plasma potassium can of course be corrected by oral or intravenous injection. But there appears to be another treatment which merits more research. Among all the medicinal plants those of the Artemisia family have the highest potassium content. The first to report this were E Brisibe, P de Magalhaes, J Ferreira et al, (Food Chemistry, 2008, 115, 1240-46). Potassium concentrations in Artemisia annua are 10 to 100 times higher than those of other minerals. A study in Morocco measured the potassium content of four medicinal plants. For Artemisia herba alba it is the highest (R Imelouane et al., J Mater Envir Si 2011, 2, 104-11).  A more complete study in Pakistan, comparing 10 medicinal plants finds that potassium content in Artemisia annua is the highest (I Hussain et al., World Appl Sci J., 2011, 12, 1464-1468). A Tunesian study finds higher concentrations of potassium in Artemisia herba alba and A campestris than in Rosmarinus or Thymus. An extensive study at the University of Islamabad analyzed the elemental content in 17 indigenous species of Artemisia that are commonly used against ailments in Pakistan.  (A. scoparia, A. absinthium, A. indica, A. santolinifolia, A. maritime, A. vulgaris, A. japonica, A. nilagirica, A. herba-alba, A. annua, A. brevifolia, A. moorcroftiana, A. dracunculus, A. roxburghiana and A. dubia. In all potassium concentrations are high in a fairly narrow range around 16 000 ppm  and most of them are known to have antimalarial properties (M Ashraf et al., J Med Plant Res 2010, 4, 2256-63).In our own research work with the University of Dakar (T Alassane et al., Afr J Biotech, 2013, 12 4179-86) we had found that the concentrations of potasssium in Artemisia annua from different origins was twice as high as in Camelia sinensis.

Many research efforts on Artemisia probably have missed this point because they work with extracts obtained in organic solvents. Only aqueous infusions and powdered leaves in capsules or tablets will deliver this essential constituant to malaria patients. The well known therapeuticac efficacy of all genotypes from the large Artemisia  family against many diseases mght to a large extent be related to their high concentration in potassium. Hypokalemia (plasma potassium concentrations below normal range) have been recognized over recent years to be very frequent in malaria and not only in severe malaria. In a study of 1415 patients in Thailand 44% of the patients infected by Plasmodium falciparum and Plasmodium vivax were hypokalemic (V Thanachartwet et al., Trop Doct 2008, 38, 155-157) Similar percentages were found in India (H Jasmin et al., J Clin Diagnostic Res, 2012, 6 678-681). And in Nigeria (J Ebele et al., Int J Trop Med, 2010, 5, 46-49). And in Kenya (K Maitland et al., Pediatric Crit Care Med, 2004 Jan 5, 81-85). Potassium deperdition is enhanced by vomiting and diarrhoea.



Submitted by Marc Vanacker (not verified) on

The antioxidant efficiency of Artemisia annua has been described in several papers. More recently in Nigeria (P Chuckwurah, A Brisibe et al., Asian Pacific J of Trop Biomed., 2014. 4, 592-598). Artemisia afra even has stronger antioxidant properties (VUB, unpublished data). The mechanism of this action is not well understood and very complex.

Potassium is known for its antioxidant properties (H Matsui et al, Hypertension, 2006, 48, 225-231), (K Ando et al., Curr Vasc Pharmacol, 2010, 8, 59-63), (Makiko Kido et al Hypertension, 2008, 51, 225-231).

As the concentration of potassium in Artemisia herb is exceptionally high, could this to some extent explain the antioxidant properties and related health benefits.

Submitted by Irene Teis on

On invading an uninfected human erythrocyte Plasmodium falciparum enters a low sodium, high potassium environment. It establishes new permeability pathways which allow the influx of sodium and efflux of potassium until reaching levels approaching those in the extraerythrocytic plasma., or eventually higher, leading to swelling and explosion of the erythrocyte. This flow is accelerated in late stages of schizont developpement (K Waller et al., Malaria Journal, 2008, 7 :19).

Cytoplasmic calcium is essential for malaria parasite egress from infected erythrocytes. A steady increase is found to preceed this egress (S Glushakova et al., Malaria Journal, 2013 12 :41). In Toxoplasma gondii it has been obsserved that the reduction in the host cell potassium causes an increase in cytoplasmic calcium.

As long as the host cells are healthy enough to maintain their normal cytosolic ion composition, they provide a suitable environment for parasite growth and the parasite will remain in the cell. If the resources of the host cell become exhausted due to the metabolic burden, a decrease in cytoplasmic potassium is noticed and this signal triggers the egress because the host cell can no longer support the replication and survival of the parasite (R Moudyet al., J Biol Chem. 2001, 276,41492-501).

A more recent in vitro study confirms most of these findings (A Pillai et al., Mol Microbiol 2013, 88, 20-34). The standard medium used for Plasmodium falciparum culture is human serum. It fulfills the requirement that the extracellular sodium concentration be high because the entry of sodium into infected cells is passive. When sodium is replaced by lithium or potasssium the parasite growth is interrupted. This may reflect on an indirect toxic effect of high potassium concentrations. This indirect toxicity might be related to the fact that potasium has a higher PSAC (plasmodium surface anion channel) permeability than sodium leading to osmotic lysis of infected cells. Potassium enrichment of the plasma leads to osmotical shrinkage of the infected erythrocyte, increased viscosity in the host cell cytoplasm and hemoglobin gelation. The supply of potassium acts like an antimalarial. The authors of this research work demonstrated that potassium really was an inhibitor of parasite growth, by adding sucrose to the parasite cultures. Sucrose acts as an impermeant of the PSAC channels and blocks the entry of extracellular potassium into the cytosol.

The precise contribution of potassium in plasmodium merozoite maturation and invasion should be reevaluated in light of these studies.The potassium channels in apicomplexan parasites like Plasmodium, Toxoplasma, Paramecium become novel targets for anti-parasitic drugs.

Many molecules present in Artemisia plants have an effect on erythrocyte cell membrane structure, permeability and cationic channels : phytosterols (K Hac-Wydro, Chem Phys Lipids 2010, 163, 689-97), steroids ( ML Lopez et al., Mem Instit Oswaldo Cruz, 104, 683-688, 2009), saponin (R Bissinger et al., Int J Hematol 2014, 100, 51-9), scopoletin (EJ Oliveira Planta Med 2001, 67, 605-8.



Submitted by Irene Teis on

The malaria parasite Plasmodium falciparum establishes in the host erythrocyte plasma membrane new permeability pathways that mediate nutrient uptake into the infected cell. These pathways simultaneously allow Na+ influx, causing [Na+] in the infected erythrocyte cytosol to increase to high levels.
The intraerythrocytic parasite itself maintains a low cytosolic [Na+] via unknown mechanisms and extrudes Na+ against an inward gradient via PfATP4, a specific parasite plasma membrane protein
This pfATP4 pump plays a critical role for plasmodium and other apicoplasts. During the asexual life cycle of Plasmodium falciparum it shows a 5-fold increase from the ring stage to the merozoit stage ( S Krishna et al., J of Biol Chem 2001, 276-14)
Scopoletin is a key constituent of many Artemisia species and probably contributes to their antimalarial efficiency. It has a significant effect on erythrocyte membrane ATPases and is likely to inhibit some of the mechanisms implemented by the parasite to regulate sodium, potassium ans calcium concentrations for its development and reproduction. Scopoletin particularly activates the Na-K-ATpase and to a lesser extent the Ca-ATPase and the Mg-ATPase at µM concentrations (C.A Ezeokonkwo et al., Nig J Nat Prod and Med, Vol 05, 2005, 37-40)