Antimalarial efficiency of Artemisia absinthium and sieberi

Artemisia absinthium and A sieberi: forgotten antimalarials Reference to Artemisia absinthium as medicinal plant is found in Egyptian papyri, early Mesopotamian texts and in many parts of the Bible e.g Deuteronomy 29:18, Proverbs 5:4, Jeremiah 9:15, Lamentations 3:15, and Amos 5:7. Artemisia afra, Artemisia herba alba, Artemisia sieberi, Artemisia absinthium have been and are still widely used as antimalarials. Some of them contain molecules like luteolin, santonin or nerolidol which have properties equivalent to quinine. They all contain a broad range of essential oils, polyphenols, coumarins, polysaccharides, saponins which differ from species to species. But the question remains: what could be a common constituent which raises the antimalarial efficiency of these plants above others. They are all characterized by a high bitterness. Since Greco-Roman times bitter tastants have been used in Europe to treat all kind of disorders, yet no pharmacological mechanism has been identified which can account for this practice. There are sweet (T1R) and bitter (T2R) taste receptors on enteroendocrine cells. Nitric oxide production is stimulated by bitter taste. Catia Sternini, L Anselmi E Rozengurt. Enteroendocrine cells: a site of ‘taste’ in gastrointestinal chemosensing Curr Opin Endocrinol Diabetes Obes. 2008 Feb; 15(1): 73–78. It appears that α-thujone and β-thujone represent the major constituent of all these Artemisia varieties, sometimes more than 50% of the total essential oil. Thujone is known for the augmentation of humoral and cell mediated immune responses. Siveen KS, Kuttan G Augmentation of humoral and cell mediated immune responses by Thujone. Int Immunopharmacol. 2011 Dec;11(12):1967-75. doi: 10.1016/j.intimp.2011.08.006.) In Ethiopia, it was found that Artemisia absinthium contains nerolidol, a powerful antimalarial. Nibret E, Wink M. Volatile components of four Ethiopian Artemisia species extracts and their in vitro antitrypanosomal and cytotoxic activities. Phytomedicine. 2010;17:369–374. doi: 10.1016/j.phymed.2009.07.016.) Evidence that thujone is the active antimalarial molecule in many artemisia species was documented in a recent paper from the Pasteur Institute of Iran. Artemisia absinthium extract has an antiplasmodial IC50 of 0.19 µg/mL vs 0.40 for chloroquine. But Artemisia dracunculus which contains no thujone has no noticeable antimalarial activity ( >200 µg/mL). Artemisia vulgaris and Artemisia khorassanica contain small quantities of thujone and show moderate antiplasmodial activities. Many recent studies also find that the anti-cancer properties of several plants, including Artemisia absinthium, are proportional to the concentration of thujone Raktim Biswas,1 Sushil Kumar Mandal,1 Thujone-Rich Fraction of Thuja occidentalis Demonstrates Major Anti-Cancer Potentials: Evidences from In Vitro Studies on A375 Cells) Recent work at the Universities of Leiden and Liege supports the thujone hypothesis. The apolar fractions of both Artemisia afra and Artemisia annua showed activity against P. falciparum. Thujone is insoluble in water. To take full advantage of the essential oil thujone which is not water soluble, it would thus be preferable to administer the plant, not in the form of an infusion, but as dry powder in capsules. Other plants like wild sage (Salvia officinalis) contain large amounts of thujone and are potential anti-malarial drugs S. Jaber and M. Akkawi, Potential Antimalarial Activity from Alcoholic Extracts of Wild Salvia palaestina Leaves, British Journal of Pharmacology and Toxicology 4(5): 201-206, 2013 ISSN: 2044-2459; e-ISSN: 2044-2467) It has been shown that Artemisia absinthium is hepatoprotective in vivo, reduces the enzymes ALAT and ASAT. Reduces lipid peroxidation, reduces TNF-alpha Nurmuhammat Amat, Halmurat Upur, In vivo hepatoprotective activity of the aqueous extract of Artemisia absinthium L. against chemically and immunologically induced liver injuries in miceJournal of ethnopharmacology 131(2):478-84 · September 201 DOI: 10.1016/j.jep.2010.07.023 Artemisia absinthium has strong antinociceptive properties close to those of morphium. M Shams, F Zeraati, K RazzaghiTopical antinociceptive effect of Artemisia absithium extract in male miceISHS Acta Horticulturae 964: International Symposium on Medicinal and Aromatic Plants IMAPS2011 DOI: 10.17660/ActaHortic.2012.964.31 Thujone also leads to an augmentation of the humoral and cell mediated immune responses. The molecule is well known for its bactericidal and vermicidal properties. This may explain why Artemisia herba alba is extensively used in Algeria. The first study on the antimalarial effect of Artemisia absinthium was published in 1990 M M Zafar, M E Hamdard, A Hameed, Screening of Artemisia absinthium for antimalarial effects on Plasmodium berghei in mice: a preliminary report. J Ethnopharmacol 1990 Sep;30(2):223-6) The highest suppression (96%) of Plasmodium berghei infected mice was observed with the ethanolic extract given orally in a concentration of 74 mg/kg. Artemisia absinthium is rich in nerolidol and davanone. Antiplasmodial effects of Artemisia absinthium have also been noticed by a research group in Cuba Aymé Fernández-Calienes Valdés, Judith Mendiola Martínez, Ramón Scull, In vitro anti-microbial activity of the Cuban medicinal plants .Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 103(6): 615-618) The inhibition of Plasmodium with extracts from the Artemisia ludoviciana from Mexico, very similar to Artemisia absinthium is up to 98,6%. The plant does not contain artemisinin. Malagon F, Vazquez J, Delgado G, Ruiz A: Antimalarial effect of an alcoholic extract of Artemisia ludoviciana mexicana in a rodent malaria model. Parasitologia. 1997, 39: 3-7 In a recent study the hydro-ethanolic extract of 5 Artemisia species were screened for their antiplasmodial and toxicity properties (A absinthium, A scoparia, A annua, A vulgaris, A dracunculus). A. annua and A absinthium showed the best activity in vitro and also reduced parasitemia in vivo in female BALB/C mice, but A absinthium was up to 64 times more potent than A annua. This is probably related to the essential oils present in A absinthium. Or to the high concentration of caffeoquinic acid. All five species analyzed contain the common flavonoids present in the Artemisia genus. A absinthium is very rich in quercetin, a molecule absent in Artemisia annua, and known for its antimalarial properties. Ali Raazani, Soroush Sardari, Behrouz Vaziri. In vitro antiplasmodial and phytochemical study of five Artemisia species from Iran and in vivo activity of two species, Parasitology Research. August 2010, Volume 107, Issue 3, pp 593–599 A similar study in 1991 already had shown the in vitro and in vivo that A absinthium acted more potently than A annua. This superiority of Artemisia absinthium against other diseases has been confirmed against Leishmania major in Iran. Among the extracts in different solvents of eleven artemisia species Artemisia absinthium is ranking among the best, better than Artemisia annua. P. Misra, N. L. Pal, P. Y. Guru, J. C. Katiyar & J. S. Tandon , Antimalarial Activity of Traditional Plants against Erythrocytic Stages of Plasmodium berghe, International Journal of Pharmacognosy Volume 29, 1991 Pages 19-23) In vitro trials in Pakistan confirmed the efficacy of Artemisia absinthium against Plasmodium falciparum. S Irshad, A Mannan, B Mirza, Antimalarial activity of three Pakistani medicinal plants, Pak J Pharm Sci vol 24, No4, 2011, 589-591. Seyed Ahmad Emami, Shahrzad Zamanai Taghizadeh Rabe, Ali Ahi, and Mahmoud Mahmoudi. Inhibitory Activity of Eleven Artemisia Species from Iran against Leishmania Major ParasitesIran J Basic Med Sci. 2012 Mar-Apr; 15(2): 807–811. PMCID: PMC3586874) In vivo trials with oral administration of Artemisia absinthium (sodiroi) on Aotus nancimae monkeys infected with Plasmodium falciparum gave an efficiency similar to 10 mg artesunate W A Sagastegui Guarniz, Estudio fitoquimico de las hojas de Artemisia absinthium y su actividad antimalarica, tesis, Universidad Nacional de Trujillo, 2009. The activity of the methanolic extract of Artemisia absinthium against Trypanosoma brucei was more efficient than those of Artemisia annua, abyssinica, afra. It was even more potent than pure artemisinin. The trematocidal effects effect of crude ethanolic extracts of Artemisia annua and Artemisia absinthium are ranking at the top in a comparison of several medicinal plants Ferreira JF, Peaden P, Keiser, Parasitol Res. 2011 Dec; 109(6):1585-92. doi: 10.1007/s00436-011-2418-0). In all these studies the selectivity index (ratio of beneficial versus toxic properties) for Artemisia absinthium appears favorable. Several of these research groups have investigated potential toxicities of thujone and found none or little. The product even has strong hepatoprotective properties. H Nahrevanian, B Esmaeili, M Kazemi, H Nazem, M Amin, In Vivo Antimalarial Effects of Iranian Flora Artemisia khorassanica against Plasmodium berghei and Pharmacochemistry of its Natural Components, Iranian J Parasitol 5,1, 2010, 6-19). A recent study shows that thujone is not more toxic than other essential oils. Radulović NS, Genčić MS, , Randjelović PJ, Stojanović-Radić Z, Stojiljković NI. Toxic essential oils. Part V: Behaviour modulating and toxic properties of thujones and thujone-containing essential oils of Salvia officinalis L., Artemisia absinthium L., Thuja occidentalis L. and Tanacetum vulgare L. Food Chem Toxicol. 2017 May 1. pii: S0278-6915(17)30222-3. Thujone which was banned in Europe for hundred years is now again available since 10 years, as food additive, in legal quantities. History has ups and downs. The French after the conquest of Algiers in 1830 used the plant Artemisia as antimalarial for hundred years, eventually based on Artemisia herba alba which is endemic in the Maghreb. Nowadays, all these plants containing thujone make an exponential come-back, from the Artemisia absinthium of our grand-mothers to Artemisia afra. Until the year 2000 only 3 scientific papers had been published concerning this plant; over the last ten years more than 100. It is now recognized that the problems related to the popular drink “Absinthe” were related to excess alcohol and had little to do with thujone Maximum thujone levels allowed in the EU: 25 mg/kg in food prepared with sage and 35 mg/kg in alcoholic beverages prepared with Artemisia species. In 2009, the EMEA authorized Artemisia absinthium as herbal medicine. Lachenmeier, Dirk; Nathan-Maister, David; Breaux, T; Luaute, ; Emmert, Joachim (2010). "Absinthe, Absinthism and Thujone – New Insight into the Spirit's Impact on Public Health". In the United States foods or beverages that contain Artemisia species, white cedar, oak moss, tansy, or yarrow, must be thujone-free, which in practice means that they contain less than 10 mg/l thujone. Other herbs that contain thujone have no restrictions. For example, sage and sage oil (which can be up to 50% thujone) are on the Food and Drug Administration's list of generally recognized as safe (GRAS) substances. An extensive analysis of commercial Absinthii herba samples obtained from retail pharmacies of different European countries in 2000 (Estonia, France), 2001 (Hungary, Belgium, Estonia, Russia), 2002 (Estonia, Greece, Ukraine), 2003 (Scotland, Armenia, Moldova, Estonia), and 2004 (Estonia, Latvia, Lithuania, Italy, Spain, and Germany) found that the essential oil content was 0.1-1.0 % on dry matter. The average content of α-thujone was 4.1 % and for β-thujone 8.7%. For a daily dose of 5gr dried Artemisia absinthium herb in decoction this would correspond to max. 5mg/L of thujone. Which is really the maximum as thujone is a lipophilic substance not readily water soluble. Anne Orava, Ain Raal, E Arak. Composition of the essential oil of Artemisia absinthium L. of different geographical origin. Proc. Estonian Acad. Sci. Chem., 2006, 55, 3, 155–165 Thujone, well present in Artemisia absinthium, A sieberi, A afra, shows significant increases in T lymphocytes in vitro and in vivo. Siveen KS, Kuttan G Augmentation of humoral and cell mediated immune responses by thujone. Int Immunopharmacol, 2011, 12 1967-75. A recent study from Pakistan evaluated the toxicity of Artemisia absinthium against standard toxicical procedures. No significant toxicity was found in brine shrimp lethality test, hemolytic and mutagenic activity and the results showed/support that A. absinthium provides significant health benefits. It is an effective and a safe alternative source to manage a variety of diseases related to liver, heart and kidney disorders. The plant revealed complete protective effect against H₂O₂ DNA damage. Ali A, Rahman K, Jahan N, Jamil A, Rashid A, Shah SM. Protection of DNA during oxidative stress and cytotoxic potential of Artemisia absinthium. Pak J Pharm Sci. 2016 Jan;29(1 Suppl):295-9. Artemisia sieberi even contains artemisinin in some ecotypes, up to 0.2% and has in vivo efficacy. M Mahboubi. Artemisia sieberi in traditional and modern medicine. Journal of Biologically Active Products from Nature Volume 4, 2014 - Issue 2 Arab HA, Rahbari S, Rassouli A Determination of Artemisinin in Artemisia sieberi. Trop Anim Health Prod 2006, 38, 497-503 HosseinNahrevanian, Bayram Sheykhkanlooye Milan Antimalarial Effects of Iranian Flora Artemisia sieberi on Plasmodium berghei In Vivo. Hindawi Publishing 2012, Article ID 727032, doi:10.1155/2012/727032