Artemisia ketone is the major constituent of essential oil of many artemisia plants, often up to 60 %. A lot of research work has been devoted to other constituents like artemisinin, scopoletine, limonene, eucalyptol, borneol, luteolin, eupatin, casticin, but artemisia ketone is completely absent in the scientific literature. The molecule had been discovered in Artemisia annua in 1938 ( WA Jacobs et al., Annual Review of Biochemistry 7,1-193) but then fell into oblivion.
When Artemisia annua was rediscovered during the Vietnam war the plant entered into the limelight. But the Vietnamese soldiers were cured by drinking the herbal infusion, not by monotherapy with artemisinin pills. This molecule only became of interest in the nineties when chloroquine resistance became overwhelming. In monotherapy artemisinine was not very efficient due to recrudescence problems so it had to be combined with antimalarial molecules like amodiaquine or lumefantrine.
Many other molecules present in Artemisia annua, like saponins, polysaccharides, scopoletin, essential oils which work in synergy with artemisinin were simply ignored. A catastrophic error: ACT pills now lead to resistance, but all the clinical trials which have been made with Artemisia annua infusion or powdered leaves never have shown any sign of resistance.
Our attention was attracted upon artemisia ketone, by a recent paper from Serbia ( NS Radulovic et al, Food and Chemical Toxicology, 2013, 58, 37-49) where they show that artemisia ketone has a stronger free radical scavenging effect and a stronger antimicrobial activity than other well known monoterpenes in Artemisia annua. It is important also to remember that thujone is a ketone with strong antimalarial properties and is present in significant concentrations in most artemisia species.
Our interest was further raised when we read in another recent paper (DN Ruskin et al., PlosOne, 2009, 4-12, e8349) that ketones can reduce pain and inflammation. We had noticed ourselves that during surgical interventions Artemisia annua has an antinociceptive effect ( M Onimus, P Lutgen et al., Med Aromat Plants, 2013,2.3), but we were not able to relate this precisely to one or several molecules. The PlosOne paper relates the antinociceptive effect to ketones, as they are generated in a ketogenic diet. The restricted carbohydrate content of ketogenic diet minimizes glucose metabolism and produces ketone bodies as alternate energy sources for heart and brain. The heart almost exclusively relies on lipid metabolism while plasmodium during its erythrocytic stages produces its energy mainly through anaerobic glycolysis. Methylglyoxal is produced in larger quantities during glycolysis and is highly toxic. The most common pathway for methylglyoxal detoxification is based on glutathione which converts it to lactate. Lipids are more efficient than glucose to produce ATP, without leaving as much “garbage”. The byproduct of ketogenesis is acetone which is eliminated in urine or breath.
The name given to artemisia ketone may be misleading. It is a small linear molecule which is not parent of heavier molecules with several rings like artemisinic acid, arteannuin B or artemisinin.
People living in the poorest countries are the most vulnerable to malaria and this may be related to nutrition. Their basic staple is rich in carbohydrates (starch) and poor in proteins and fat. The main source of energy is thus glucose and not ketone bodies. But glucose is food for plasmodium which needs 60 times more of this fuel than the healthy erythrocyte. Fatty, ketogenic diet will provide less nutrients to the parasite although this has not been explored in depth. Breastfeeding seems to contribute to the immunity of newborns during 6 months and breast milk is rich in fat. Ketone bodies may even inhibit parasite proliferation. Dihydroxyacetone, which is an energy source in human cells, is antiproliferative in chloroquine-sensitive and resistant strains (S Pavlovic et al., Biochim Biophys Acta 2006, 1758, 1012-7).
A range of ketones act as antimalarials, for example chalcones. They inhibit the plasmodial cysteine protease enzyme. In in vivo trials run in India (S Marhajan et al., Parasitology, 2005, 131, 459-466) five ketones out of twenty showed good antimalarial activity, when tested individually. Nine out of twenty showed good activity, when tested in combination with rufigallol. Some chalcone-chloroquine hybrid pharmacophores showed in vivo suppression of 99.9 % of Plasmodium falciparum parasitemia on day 4 in mice ( KV Sashidara et al., Biorg Med Chem 2012, 20-9, 2971-81). It is likely that ketone bodies also work synergistically with other antimalarials, but it is possible that they are antimalarials per se. Several plants of the Asteraceae family well known as medicinal plants are rich in the ketone davanone: Artemisia pallens, persica, sieberi, herba alba, capillaris.
The effect of ketogenic diet might also explain many anecdoctical results on the effect of lipids on Artemisia annua efficiency. In 2009 at the 2d Symposium on Tropical Diseases at Luxembourg, D Rezelman showed that the addition of arachid oil enhanced the efficiency of Artemisia annua extract by a factor 3 in mice. The Brewer Science Library reports that some physicians recommend to take artemisinin with whole milk, cod liver oil, almond oil or flaxseed oil. At the ICEI malaria conference at Roma in April 2010 B Isacchi from the Universitate di Firenze showed that olive extract enhanced the effectiveness of artemisinin. In 2011 clinical trials run by IFBV-BELHERB in Dagana, Senegal showed that a mixture of Artemisia annua leaf powder and peanut butter gave cure rate > 95%. Dr F Roelofsen (personal communication, 2012) showed that when Artemisia annua leaves mixed with 10% fatty yoghurt gave a higher AUC and an extension of half-life for artemisinin from 30 minutes to 2-3 hours .
There are several pathways to explain the positive effect of lipids delivered in conjunction with tea. It is possible that an oil rich diet has an effect on the erythrocyte membrane lipid composition, stimulation of calcium channels and permeability (A Pagnan et al., Clinical Science, 1989, 76, 87-93). Lipids may increase the bioavailability of lipophilic substances like artemisinin or essential oils. This effect has been documented for lumefantrine (EA Ashley et al., Trop Med Internat Health, 12, 2007, 195-200). The University of Louvain develops lipid-based drug delivery systems for arteether ( PB Memvanga et al., Eur J Pharma and Biopharmaceutics, 2012, 82, 112-119).
A Japanese paper ( H Kurikara et al., Biosci Biotechnol Biochem, 66, 1955-58, 2002) shows that Camellia sinensis tea accelerates the lipid metabolism like a catalyst. A very recent paper from Korea (DW Lim et al., Molecules 2013, 18, 9241-9252) documents similar effects for Artemisia capillaris. Their results show that extracts of this plant enhance the lipid metabolism, reduce cholesterol, reduce hepatic lipid contents and the serum ALAT and ASAT levels. Many studies document the lowering effect of several Artemisia species on cholesterol and triglycerides.
This may be a key mechanism in malaria therapy which has been barely investigated. Human HDL cholesterol is necessary for P falciparum in in vitro culture (D Bansai et al., Lipids in Health and Disease, Biomed Central, 2005, 4-10). In vivo Plasmodium continuously diverts cholesterol from hepatocytes and erythrocytes which leads to a lower cholesterol level in malaria patients ( UM Chuckwuocha et al., Asian Pac J Trop Med., 4-12, 2011, 993-4). In malaria endemic areas significantly lower levels of cholesterol and triglycerides were found in children infected with P falciparum. But further studies are needed for better understanding of the mechanism of lipid break-up by the parasites, because they are in competition with the energy needs of the human body.
With our partner in Senegal (T Alassane et al., Afr J Biotech 12:26, 4179-86, 2013), we made an analysis for the microelements present in Artemisia annua and Camellia sinensis samples from different origins. Both herbs are very similar in content and contain more essential elements than other vegetables. In starved and stressed mice the half-life of intravenously injected soybean oil was reduced to 35 min when Camellia sinensis tea was administered. This is a boost in energy for the organism because lipids deliver 10 times more energy than glucose. This might also apply to patients debilitated by malaria infection.
A lower glucose level in the blood will open the door for an enhanced lipid metabolism. All artemisia species seem to have a hypoglycemic effect. Treatment of rats with Artemisia annua aqueous extract reduced the serum glucose after 4 weeks from 110 to 70 mg/mL (TB Mojarad et al., Iranian Biomedical Journal, 9:2, 2005, 57-62). In South Africa Artemisia afra is extensively used for several diseases including diabetes . Methanol extracts of A. absinthium have a strong hypoglycemic and hepatoprotective activity ( BJ Goud, Int J Adv Pharmac Res., 2:7, 2011). For A. herba alba the ethanol-water extract produced stronger hypoglycemic effect than the hexane extract ( NE Awad et al., J Appl Pharmac Sc. 02:03, 2012, 30-39). A. sieberi has been studied for a similar effect in Iran.
There is also the unknown effect of phytosterols present in Artemisia plants. A thesis from Romania ( B Ivanescu, PhD Thesis, 2010) finds a high concentration of plant sterols in Artemisia annua, vulgaris and absinthium, mostly beta-sitosterol. Artemisia apiacea also contains artemisterol. The richest naturally occurring sources are vegetable oils and nuts, like peanuts or avocado kernels. Also in milk and yoghurt. Often beta-sitosterol concentration is higher in the dry part of the plant, stems rather than leaves. The structure of beta-sitosterol and cholesterol are quite similar. It is reasonable that beta-sitosterol can inhibit the absorption of cholesterol in the body. This effect was first demonstrated in humans in 1953. And is one of the reasons beta-sitosterol is added to some margarines. It may be related to biological reasons or simply to physical competition in solubility in aqueous media: beta-sitosterol precipitates cholesterol from solution ( L Christansen et al., Int J Pharm., “003, 244-2, 155-166). Several studies have investigated the anticancer properties of beta-sitosterol, ( N Plana et al., European J Nutrit., 47-1, 32-9, 2008) (AB Awad et al., Nutr Cancer, 2000, 238-41). An important side-effect of beta-sitosterol are its larvicidal properties which have been studied in several papers ( A Ghosh, Asian J Trop Disease, 2013, 3-3, 252)
All this might apply for artemisia ketone and phytosterols in artemisia herbal medicine. Recently there has been a lot of controversy on the use of raspberry ketones as fat burners for weight loss. Artemisia ketone is similar is similar in structure to raspberry ketones and chalcones. Its intestinal absorption should be high. Artemisia annua from Luxembourg is very rich in artemisia ketone, probably because it is a wild chemotype similar to the one from Serbia studied by Radovic. It might also be related to lower drying temperatures at 35°C compared to temperatures of 65°C used in industrial processes (S Khangolil et al., Pak J Biol Sci 2008, 15:11, 934-7). High artemisinin hybrids do not contain any artemisia ketone (L.Pace et al., Proc 53d Ital Soc Agricult Genet 16/19 Sept 2009). In studies on inflammation the plant from Luxembourg shows higher inhibition of IL-6 and IL-8 than Artemisia annua plants from other origins (PM de Magalhaes et al, Food Chemistry, 2012) and in several clinical trials run by IFBV-BELHERB in Africa it always gives cure rates > 95% at day 7, despite its extremely low artemisinin content of 0.1%. The high artemisinin hybrid A3 used in the controlled trials in Congo in 2004 only gave a cure rate of 74% at day 7 (MS Mueller et al Trans R Soc Trop Med Hyg 2004 98:5, 318-21). We bought several samples of Artemisia annua herb of Chinese origin in pharmacies in Luxembourg and Germany. The average artemisine content is 0.08% and the artemisia ketone content is very high at 42% of the essential oil. An analysis of Chinese Artemisia annua reported in 1990 even gives a value of 66.7 % (JE Simon et al., Advances of new crops, Timber press, Oregon, 1990). Artemisia afra is used as antimalarial in East and South Africa. Some chemotypes of this plant are very rich in artemisia ketone (S L Chagonda et al., Flavour and Fragrance Journal, 14-2, 1999) Artemisia apiacea in old Chinese documents has the reputation to be more effective than Artemisia annua against malaria. It contains a lot of artemisia ketone but is very, very poor in artemisinine. Artemisia ketone definitely deserves more attention