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Do Artemisia annua and artemisinin have a hormetic effect?

December 18, 2016 - 08:03 -- Pierre Lutgen

 

“All things are poison and not without poison; only the dose makes a thing not a poison” Philippus Aureolus Theophrastus Bombastus von Hohenheim, also known as Paracelsus (1493–1541).

Hormesis is the term that describes any process in a cell or organism that exhibits a biphasic response to exposure to increasing amounts of a substance. Within the hormetic zone there is generally a favorable biological response at moderate exposures and a negative impact at very low or at high doses. In the case of natural compounds an example of hormesis is vitamin A which in relatively low amounts is essential for normal development and eye function, but in high amounts can cause anorexia, headaches, drowsiness, altered mental states and other symptoms. Another well known example, the hormetic effects of wine drinking

The hormetic effect for the antimalarial methylene blue on locomotor activity and memory has been described in rats. The optimal dose for intraperoneal injection is 1-10 mg/kg. The effect at lower or higher doses did not differ from the baseline.

          Penny D Riha, Aleksandra K Bruchey Memory facilitation by methylene blue: Dose-dependent effect on behavior and brain oxygen consumption. European Journal of Pharmacology 511(2-3):151-8· April 2005 DOI: 10.1016/j.ejphar.2005.02.001 ·

The strong antimalarial hypoestoxide, extracted from Hypoestes rosea in Nigeria, also shows a clear hermetic effect with an optimal dose at 200 µg/kg in mice.

          E Ojo_Amaize, E Nchekwube, J Okogun. Plasmodium berghei: Antiparasitic effects of orally administered Hypoestoxide in mice. Experimental Parasitology 2007 117, 218-221.

Artemisia annua is able to sterilize water. In 2008 a research team at Luxembourg found that adding fresh Artemisia annua tea, even to heavily contaminated water, had a stronger bactericidal effect than boiling the contaminated water for 5 minutes or irradiating it for 10 minutes under a 365 nm UV lamp.

           P. Lutgen. B Michels, Proceedings International Conference, Luxembourg June 3-4 2008

This effect was confirmed by several other laboratories, at the University of Bangui, at the University of Gent, at the University of Antioquia, at the University of Dakar. The bactericidal effect was supposedly related to artemisinin. Until the Universities in Medellin and Bangui found that after 24 hours this bactericidal property had vanished. The bacterial concentration was even increasing in the infusion.  A possible explanation is that artemisinin only plays a minor role but that the initial high concentration of hydrogen peroxide in the infusion vanishes in a few hours and that the remaining organic matter of the plant acts as food for the bacteria.

           Mobili OB Mabingui J, Nola M, Synergistic effect of light, pH and Artemisia annua extract on Enteroccus faecalis. Int J Applied Microobiol Biotech Res. 2015, 362 72.

            Marıa Cecilia Escobar, Yamilet Arcos. Efecto microbicida de laradiacion solar(SODIS) combinado con Artemisia annua, Universidad de Antioquia, submitted

The Université des Montagnes in Cameroon has shown that tea Artemisia annua is hepatoprotective. On the other hand, some studies have shown that the high doses of artesunate prescribed by the ACT treatment are hepatotoxic. The same recent research work from the Université des Montagnes shows that in infusions the concentration of artemisinin reaches a plateau in function of increasing quantities of dry herb.

In clinical trials which were run in Kenya and in Katanga no dose effect was notices in the range administred. In other words, low doses were as efficient as high doses.

           Whole-Leaf Artemisia annua based Antimalarial Drug, ICIPE, KEMRI and NUSAG project. April 2005 Nairobi Kenya.

           C Kansango Tchandema P Lutgen. , In vivo Trials on the Therapeutic effect of encapsulated Artemisia annua and Artemisia afra, Global J Res Analysis, 2016, 5(6) ISSN 2277-8160

Artemisia annua also displayed hormesis in the treatment of osteoarthritis. Statistically significant reductions for stiffness and pain were seen from baseline in the Artemisia annua low-dose group. No statistically significant changes occurred in the placebo or in the high-dose groups for any parameter.

            Stebbings, S., Beattie, E., McNamara, D. A pilot randomized, placebo-controlled clinical trial to investigate the efficacy and safety of an extract of Artemisia annua administered over 12 weeks, for managing pain, stiffness, and functional limitation associated with osteoarthritis of the hip and knee. Clin Rheumatol (2016) 35: 1829. doi:10.1007/s10067-015-3110-z

At the University of Al Quds it was noticed that the addition of calcium carbonate enhanced the inhibitory effect of Artemisia annua on beta-hematin formation.

           Suhair Jaber, Saleh Abu-Lafi, Pierre Lutgen, Mutaz Qutob, Qassem Abu-Remeleh and Mutaz Akkawi. Bicarbonate  effect on Beta-Hematin Inhibition by Artemisia Sieberi Aqueous Infusion Journal of Pharmacy and Pharmacology 3 (2015) 63-72 doi: 10.17265/2328-2150/2015.02.003

Université de Liège-Gembloux noticed a concentration effect of the insecticidal properties of Artemisia annua infusions.

There are strong synergistic and antagonistic effects between the different constituents of Artemisia annua,

            X 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

The allelopathic properties of   Artemisia annua seem to depend on artemisinin concentration and the presence of other substances.

           R Belz, K Hurle, A Challenge in Allelopathy, Nonlinearity in Biology, Toxicology, and Medicine, 3: 173–211, 2005

         J Lydon, JR Teasdale, PK Chen, Allelopathic activity of annual wormwood (Artemisia annua) and the role of artemisinin, Weed Science, 1997, 45. 807-811.

US patent 5578637 (Lai H. Singh N, University of Washington, 1996) states that artesunate stimulates the immune system at low doses and inhibits it at high doses.

This is in line with a recent paper from Iran. Extracts of different parts of 7 Artemisia species increased PBMC number in a dose dependent manner up to 250 µg/mL. After that the effect sharply decreased. Flower extract of Artemisia sieberi increased the PBCM number up to 5 folds

          Hassan Mohabatkar,  Mandana Behbahani  Effects of root, shoot, leaf and seed extracts of seven Artemisia species on HIV-1 replication and CD4 expression J of Coastal Life Medicine, 2015 3(12) 996-999 DOI: 10.12980/jclm.3.2015j5-126

There is one study on artemisinin which clearly shows a hormetic effect. The toxic effects of artesunate and dihydroartemisinin on the growth metabolism of Tetrahymena thermophila  were studied by microcalorimetry. The results showed that: low concentrations of artesunate (<or=1 mg L(-1)) and dihydroartemisinin (<or= 2 mg L(-1)) promoted the growth metabolism of T. thermophila BF5, whereas high concentrations of artesunate (1-60 mg L(-1)) and dihydroartemisinin (2-60 mg L(-1)) inhibited its growth.

           Shen XS, Su Q, Qiu ZP, Xu JY, Xie YX, Liu HF, Liu Y. Effects of artemisinin derivative on the growth metabolism of Tetrahymena thermophila BF5 based on expression of thermokinetics. Biol Trace Elem Res. 2010 Jul;136(1):117-25. doi: 10.1007/s12011-009-8527-2

           AJ Vargas. Hormesis and Synergy: Pathways and Mechanisms of Quercetin in Cancer Prevention and Management. Nutr Rev 68 (7), 418-428. 7 2010

Scopoletin well present in Artemisia plants demonstrates hormetic effects.

  YONG Xiao-Ju ZHANG Yong-Qiang DING Wei. Repellent and oviposition deterrent properties of scopoletin to Tetranychus cinnabarinus Chinese Journal of Applied Entomology 2012-02

Condensed tannins also exert a hormetic effect and they are well present in Artemisia plants

De Nicola E, Gallo M, Iaccarino M, Meriç S, Oral R, Russo T, Sorrentino T, Tünay O, Vuttariello E, Warnau M, Pagano G. Hormetic versus toxic effects of vegetable tannin in a multitest study. Arch Environ Contam Toxicol. 2004 Apr;46(3):336-44.

                                                                                                 Antioxidants: friends or foes?

Quercetin is a unique dietary polyphenol because it can exert biphasic dose-responses on cells depending on its concentration.  Antioxidant properties are observed at concentrations of approximately 1-40 microM. Pro-oxidant effects are present at cellular concentrations of 40-100 microM.  Other flavonoids also may generate oxidants.=1>

           =1>Miura YH, Tomita I, Watanabe T, Hirayama T, Fukui S. Active oxygens generation by flavonoids. Biol. Pharm. Bull. 1998;21:93–96 

           Prochazkova D, Bousova I, Wilhelmova N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011;82:513–523. =1>

           Chobot V, Kubicova L, Bachmann G, Hadacek F. Versatile redox chemistry complicates antioxidant capacity assessment: Flavonoids as milieu-dependent anti- and pro-oxidants. Int. J. Mol. Sci. 2013;14:11830–11841. =1>

           Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 1996;20:933–956 =1>

Addition of polyphenol rich beverages like coffee or tea to commonly used cell culture media generate substantial amounts of hydrogen peroxide. =1>

           Akagawa M, Shigemitsu T, Suyama K. Production of hydrogen peroxide by polyphenols and polyphenol-rich beverages under quasi-physiological conditions. Biosci Biotechnol Biochem. 2003 Dec;67(12):2632-40. =1>

           Long LH, Halliwell B. Coffee drinking increases levels of urinary hydrogen peroxide detected in healthy human volunteers. Free Radic Res. 2000 May;32(5):463-7the erythrocytic stages of its life cycle. It does it by expelling from the erythrocyte the NO producing arginine and importing antioxidant enzymes. Recent findings have shown that in addition to these redox systems the parasite also has an important mitochondrial antioxidant defence system and it is suggested that lipoic acid produced by the apicoplast plays a pivotal part. To kill Plasmodia, we need pro-oxidants like artemisinin, chloroquine, ROS, hydrogen peroxide, but certainly not anti-oxidants like vitamin E and C. =1>

But the hormesis curve may be different for parasites and for humans. The answer eventually is described in a paper from Taiwan. =1>

          N. C. Yang, C. H. Lee, and T. Y. Song, “Evaluation of resveratrol oxidation in vitro and the crucial role of bicarbonate ions,” Bioscience, Biotechnology and Biochemistry, vol. 74, no. 1, pp. 63–68, 2010 =1>

Polyphenols can oxidize in the culture medium BME (Basal Media Eagle) to generate hydrogen peroxide. Generally, sodium bicarbonate is used during preparation of the medium for trials to raise and stabilize pH. The authors worked with resveratrol and the gallate EGCG. With BME containing bicarbonate there is a rapid and almost total degradation of the two polyphenols. But when they replace bicarbonate by a mixture of vitamins, or other inorganic salts or amino acids no degradation occurs. There is no degradation in butanol or butanol saturated with bicarbonate. Milli-Q water has no effect on degradation, nor sodium phosphate nor glucose added to this water, but the addition of 2,2 g/L of sodium bicarbonate to water leads to a rapid and total degradation of these polyphenols. The degradation goes along with the production of hydrogen peroxide. This generation is proportional to the concentrations of bicarbonate in water.=1>

                                                    Digestion and gut permeability

Most medicinal plants have a bitter taste, which is quite variable depending on geological and climatological conditions. This influences the postprandial haemodynamics and influences digestion

                MK McMullen, JM Whitehouse, A Towell.  Bitter tastants alter gastric-phase postprandial haemodynamics, J Ethnopharmacology  2014 submitted.

Biological variations among patients -- due to variations in stomach acidity and other factors -- can reduce the effectiveness of oral drugs. The team of an American pharmaceutical company  showed that Sprite seemed to control stomach acidity in a way likely to allow greater absorption of the drug into the body. Based on the results, the scientists suggest that patients in future clinical trials take the drug with Sprite.

                Christopher S. Polster, Faraj Atassi, Sy-Juen Wu, David C. Sperry. Use of Artificial Stomach-Duodenum Model for Investigation of Dosing Fluid Effect on Clinical Trial Variability. Molecular Pharmaceutics, 2010; 7 (5): 1533 DOI: 10.1021/mp100116g.

Lime juice also has an influence on the efficacy of antimalarial drugs. One hundred and twenty children with acute uncomplicated malaria children were randomized into treatment with ACTs either alone or with lime juice. The average time to achieve >75% reduction in parasite load was significantly lower in patients on ACT and lime; Also, while a significantly higher proportion of children on antimalarial drugs and lime juice achieved complete parasite clearance by 72 h of therapy ten (18.2%) patients without lime had early treatment failure.

                 Adegoke SA1, Oyelami OA, Olatunya OS, Adeyemi LA. Effects of lime juice on malaria parasite clearance. Phytother Res. 2011 Oct;25(10):1547-50. doi: 10.1002/ptr.3418

                                                                                                     The role of the red cell membrane =1>

The cell membrane is considered by many biologists as the brain or doorkeeper of the cell. For Plasmodium falciparum which is imbedded in this cell, this membrane plays a vital role. The parasite leads to a huge increase in solute traffic across the membrane of a normally tight cell. The infected (iRBC) red blood cells also has a higher permeability for other substances, like folates, isoleucine, but especially for glucose and hexose. =1>

             Woodrow CJ, Penny J, Krishna, Intraerythrocytic Plasmodium falciparum expresses a high affinity facilitative hexose transporter J Biol Chem 274, 1999, 7272-77 =1>

Artemisinin enters irreversibly into the red blood cells. It does not bind to RBC membranes =1>

             T Gordi, A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction PhD thesis 2011. =1>

It is metabolized faster in pregnant women. A variety of otherwise impermeant substances such as carbohydrates, polyols, amino acids gain easily access. Artemisinin preferentially enters into the infected RBC. =1>

            Vyas N, Avery BA, Avery MA, Wyandt CM. Carrier-mediated partitioning of artemisinin into Plasmodium falciparum-infected erythrocytes. Antimicrob Agents Chemother. 2002 Jan;46(1):105-9. =1>

The parasite needs however to dispose of toxic lactate from the food vacuole because this degradation product may lead to acidification of the parasite cytosol. The pathways opened by the parasite display porelike properties with selectivity towards anions and neutral molecules. Polysaccharides can either be neutral of form anions in the presence of salts. The entry of a variety of substrates is blocked by bio-flavonoids =1>

            Z Cabantchik, Altered membrane transport of malaria infected erythrocytes. Blood, 74, 1989, 1464-71=1>

Amino-reactive reagents also block these pores at high pH. =1>

            W Breuer, S Kutner, Z Cabantchik Covalent modification of the permeability pathways induced in the human erythrocyte membrane by the malarial parasite Plasmodium falciparum. J Cell Phys 133, 1987, 55-63 =1>

Saponins and monoterpenes have a synergistic effect in weakening cell membranes and enhancing permeability. They have haemolytic properties and develop 40-50 Angstroem pores in erythrocyte membranes. This might explain why they are extensively used as adjuvants in vaccines. They are efficient at very low doses. It is very strange that iRBCs are 27 to 1 times more resistant to saponin hemolysis than non-infected cells. Saponin is used as haemolytic solvent for erythrocyte membranes. It was noticed that membranes of Plasmodium falciparum infected membranes resist to hemolysis by saponins. But it appears to be only the case for in vitro cultures not for ex vivo iRBCs =1>

              AU Orjih, Requirements for Maximal Enrichment of viable Inthraeythrocytic Plasmodium falciparum rings by Saponin Hemolysis. Exp Biol Med 233, 2008, 1359-1367 =1>

RBCs infected by Plasmodium progressively lose their deformability. They also increase the volume of the RBC especially at the schizont stage. These are all strategies developed by the parasite to survive during 2 days in the same erythrocyte for asexual multiplication. And all this may lead to splenomegaly. =1>

Conclusion

Possible synergistic effects of the constituents in Artemisia annua have been studied extensively, but antagonistic and hormetic effects have been neglected