Malaria therapy and prophylaxy with unsaturated fatty acids

PUFA Malaria

Artemisia plants are rich in polyunsaturated fatty acids (PUFA) which generate prostaglandins and stimulate monocytes. PUFAs possess well documented antimalarial and prophylactic properties. Their half-life in plasma is several days and in adipose tissue several weeks. This may explain the prophylactic effect of regular consumption of Artemisia infusion or powder. Fish oils rich in polyunsaturated fatty acids (PUFAs) cause a marked in vitro growth inhibition of Plasmodia. Similar effects were seen in vivo on mice infected with Plasmodium berghei and treated during 4 days with these acids. The effect is not only suppressive but also prophylactic. L M Kumaratilake, A Ferrante, B S Robinson, T Jaeger, and A Poulos Enhancement of neutrophil-mediated killing of Plasmodium falciparum asexual blood forms by fatty acids: importance of fatty acid structure. Infect Immun. 1997 Oct; 65(10): 4152–4157. A very recent thesis from the French CNRS confirms that PUFAs derived from human phospholipids exert a potent in vitro anti-plasmodium activity primarily by hydrolyzing lipoproteins from plasma, thereby releasing PUFAs that are toxic to the parasite Carole Guillaume, Christine Payré, Christiane Deregnaucourt. In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A. Infect. Immun. June 2015 vol. 83 no. 6 2453-2465 An infant is usually born with a deficient immune system, and the long chain polyunsaturated fatty acids (LC-PUFA) in breast milk play an important role in the development and maturation of infant’s immune system. Foetal cord blood contains higher portions of n-3 and n-6 long-chain PUFA than maternal blood. Schlörmann W, Kramer R, Foetal cord blood contains higher portions of n-3 and n-6 long-chain PUFA but lower portions of trans C18:1 isomers than maternal blood. Food Nutr Res. 2015 Nov 27;59:29348. doi: 10.3402 It is assumed that during the blood stage of malarial infection the Plasmodium falciparum reproduces in a safe haven, the food vacuole, totally isolated from the hostile outside world of host defenses. Nevertheless, the parasite must import a multitude of substances and export others. To this effect he grossly alters the structure and composition of the host erythrocyte. The phospholipid and fatty acid compositions change. The unsaturation index is considerably lower than in uninfected erythrocytes L L Hsiao, R J Howard, M Aikawa, and T F Taraschi. Modification of host cell membrane lipid composition by the intra-erythrocytic human malaria parasite Plasmodium falciparum. Biochem J. 1991 Feb 15; 274(Pt 1): 121–132. Large increases in palmitic acid from 21.9 to 31.2, in oleic acid from 14.6 to 24.6 and major decreases in arachidonic acid from 17.4 to 7.8, in docosahexaenoic (DHA) from 4.9 to 1.8 %. The parasite, during intra-erythrocyte maturation, markedly refashions the composition of the phospholipids. GG Holz. WHO Bulletin, 1977. 55 (2) 237-248 The analysis of residual erythrocyte plasmas, food vacuoles and hemozoin identifies predominantly saturated palmitic and stearic acids, and smaller amounts of oleic and linoleic unsaturated fatty acids. Arachidonic acid is absent John M. Pisciotta, Isabelle Coppens, Abhai K. Tripathi, Peter F. Scholl, Joel Shuman, Sunil Bajad, Vladimir Shulaev, David J. Sullivan Jr. The role of neutral lipid nanospheres in Plasmodium falciparum haem crystallization Biochemical Journal Feb 15, 2007, 402 (1) 197-204; DOI: 10.1042/BJ20060986 This confirms the results of another paper Coy D Fitch , Guang-zuan Cai, James D Shoemaker. A role for linoleic acid in erythrocytes infected with plasmodium berghei Biochimica and Biophysica Acta 2000, 1535, 45-49. In Plasmodium infected mice erythrocytes, palmitic acid increased from 161 to 830 nmol/ml, stearic acid from 35 to 256, oleic acid from 73 to 260 and linoleic acid from 6 to 211 nmol/ml. When radioactive carbon labeled palmitic, stearic and oleic acids were incubated with infected rhesus monkey Plasmodium knowlesi these were incorporated into lipids of the erythrocytes, the intracellular parasites. Another author found similar increases in saturated fatty acids and decreases in PUFAs for Plasmodium iopurae in ducks, Plasmodium knowlesi in monkeys and Plasmodium berghei in rats. Arachidonic acid is reduced by 70%. G.G. Holz; Lipids and the malarial parasite; Bulletin of the World Health Organization, Volume 55, 1977, pp. 237–248 Since malaria parasites lack the capacity to synthesize fatty acids an expanded pool of short chain acids probably supplies the building blocks for those classes of lipids needed for parasite survival, and more particularly for hemozoin crystallization. For the culture of Plasmodia plasma can be completely replaced by the saturated stearic acid Siddiqui, Wasim A.; Schnell, Jerome V.; Geiman, Quentin M.Stearic Acid as Plasma Replacement for Intracellular in vitro Culture of Plasmodium knowlesi Science, Volume 156, Issue 3782, pp. 1623-1625 This has been confirmed Trigg PI. Some factors affecting the cultivation in vitro of the erythrocytic stages of Plasmodium knowlesi. Parasitology. 1969 Aug;59(3):915-24 A fatty acid mixture, rich in stearic acid was also found to be an ideal growth medium for eggs for Schistosoma mansoni eggs in vitro Newport GR, Weller TH.Deposition and maturation of eggs of Schistosoma mansoni in vitro: importance of fatty acids in serum-free media. Am J Trop Med Hyg. 1982 Mar;31(2):349-57. In 1960 already, it had been found that only stearic acid and oleic acid were satisfying the growth needs for Paramecia. Unsaturated fatty acids are inactive Miller, C. A., and W. H. Johnson. 1960. Nutrih'on of Paramecium: A fatty acid requirement. J. Protozool., 7: 297—301 Similar results were found in 1962 at Elizabethville for Trypanosoma cruzi. Stearic acid is the essential growth factor. None of the longer chain fatty acids, saturated or unsaturated, had a growth promoting effect Bone GJ, Parent G. Stearic acid, an essential growth factor for Trypanosoma cruzi. J Gen Microbiol. 1963 May;31:261–266. ((GJ Boné et al., J Gen Microbiol 1963, 31, 261-266 These are important facts in light of the absence of a stearic acid in Artemisia annua Nibret,E, Wink,M.,Volatile.components.of.four.Ethiopian Artemisia species extracts. Phytomedicine(2009),doi:10.1016/j.phymed.2009.07.016 PUFA’s in plants: Not only PUFAs from fish oil but also from plants have an effect. When comparing palm oil and corn oil with fish oil in malaria induced by Plasmodium berghei in Swiss mice Blok WL, Vogels MT, Curfs JH, Eling WM, Buurman WA, van der Meer JW. Dietary fish-oil supplementation in experimental gram-negative infection and in cerebral malaria in mice. J Infect Dis. 1992 May;165(5):898-903. it was found that cerebral malaria occurred in only 23% of fish oil-fed mice, in 61%, in the corn oil group and 81% in the palm oil group. Survival in the fish oil group was 78%, 38% in the corn oil group and 20% in the palm oil group. Artemisia annua leaves contain up to 10% of fatty acids in dry matter. EA Brisibe, Pedro M. Magalhäes,Jorge F.S. Ferreira, Nutritional characterisation and antioxidant capacity of different tissuesof Artemisia annua. Food Chemistry, 2009, 115, 1240-1246 Another author finds 6% Shahid Iqbal, Umer Younas. Chemical Composition of Artemisia annua L. Leaves and Antioxidant Potential of Extracts as a Function of Extraction Solvents.Molecules 17(5):6020-32 · December 2012. DOI: 10.3390/molecules17056020 This is extremely high, at the same level as for plants which are used for oil production, as for example flax i.e. Linum usitatissimum A de Aguiar; Sílvia Cristina de Aguiar Marcela Boroski; Nilson Evelázio de Souza; Makoto Matsushita; J Visentainer Quantificação de ácido alfa-linolênico em caules e folhas de linho (Linum usitatissimum L.) colhidos em diferentes estágios de desenvolvimento. Ciênc. agrotec. vol.34 no.6 Lavras Nov./Dec. 2010 doi.org/10.1590/S1413-70542010000600021 Another study on 39 aromatic plants finds values ranging from 0.7 to 4.5% Olívia Rodrigues Pereira, Medicinal Plants and Evaluation of Pharmacological activities Doctoral Dissertation, University of Salamanca, 2013 In forage leaves the content is 2.3%. In the medicinal plant Panax ginseng the total concentration of fatty acids is 5.1 % dw and 62% of these are PUFAs Xiao-Jing Zhang, Li-Li Huang, Xiu-Jiang Cai, Peng Li, Yi-Tao Wang, Fatty acid variability in three medicinal herbs of Panax speciesChem Cent J. 2013; 7: 12. Published online 2013 Jan 21. doi: 10.1186/1752-153X-7-12 A study on edible plants finds 1.70 for spinach, 0.60 in lettuce, 1.10 in mustard mg/g wet weight which would correspond to 1% fatty acids in dry material Simopoulos, A.P., 2004. Omega-3 fatty acids and antioxidants in edible wild plants. Biol. Res. 37,263–277 Care must be taken because leaves of medicinal plants lose most of their fatty acids during senescence Z Yang and J B. Ohlrogge Turnover of Fatty Acids during Natural Senescence of Arabidopsis, Brachypodium, and Switchgrass and in Arabidopsis β-Oxidation Mutants. Plant Physiology August 2009 vol. 150 no. 4 1981-1989 Nuts and seeds are particularly rich in PUFAs: pumpkin seeds 20.9%, sunflower seeds 23.1%, almonds, 12.1%, pistachios 13.2%, chestnuts 0.9%, hazelnuts 7.9% dw. In breast milk 90% of the fatty acids are PUFAs. Unfortunately, there aren’t many documents in the scientific literature which analyzed Artemisia annua for the content of saturated and unsaturated fats. The high content of polyunsaturated fatty acids (PUFA) in Artemisia herba alba is confirmed by feeding studies. Dietary supplementation with essential oil from A herba alba increases the content of these fats in the muscles of lambs much more than essential oil from Rosemary Vasta V, Aouadi D, Brogna DM, Scerra M, Luciano G, Priolo A, Ben Salem H. Effect of the dietary supplementation of essential oils from rosemary and artemisia on muscle fatty acids and volatile compound profiles in Barbarine lambs. Meat Sci. 2013 Oct;95(2):235-41. doi: 10.1016/j.meatsci.2012.12.021. A phytochemical analysis of five Artemisia species in Turkey shows that saturated fatty acids in these plants represent on the average 40 % of the total and the unsaturated fatty acids 60 %, including those with antimalarial activities like linoleic acid, arachidonic acid and linolenic acid Murat Kursat, Irfan Emre, Okkeş Yilmaz, Phytochemical Contents of Five Artemisia Species Not Sci Biol, 2015, 7(4):495-499. DOI: 10.15835/nsb.7.4.9683 These three PUFAs act as precursor for the synthesis of longer chain PUFAs like EPA and DHA in liver and brain. Smink W, Gerrits WJ, Linoleic and α-linolenic acid as precursor and inhibitor for the synthesis of long-chain polyunsaturated fatty acids in liver and brain of growing pigs. Animal. 2012 Feb;6(2):262-70. Fatty acids are known as self-defensive agents in organism and possess various biological activities including anti-inflammation. It is known that NF-kB activation involved in the inflammation development and the inhibition of this transcriptional factor is considered as a therapeutic target for inflammation treatment Bingzhong Xue , Zhenggang Yang, Xianfeng Wang, Omega-3 Polyunsaturated Fatty Acids Antagonize Macrophage Inflammation via Activation of AMPK/SIRT1 Pathway, 2012, doi.org/10.1371/journal.pone.0045990 An extensive review describes how PUFAs modulate the macrophage membrane domains, promote the phagocytosis rate as well as bactericidal capacity of macrophages by increasing the concentration of ROS and NO inside of the macrophage, impact their respiratory burst and down-regulate the synthesis of the pro-inflammatory cytokine IL-1β, IL-6 and TNF-α. Julia Schumann, Alexander Leichtle, Herbert Fuhrmann, Fatty Acid and Peptide Profiles in Plasma Membrane and Membrane Rafts of PUFA Supplemented RAW264.7 Macrophages, 2011.doi.org/10.1371/journal.pone.0024066 The invasion of blood by Plasmodium triggers inflammation and increases in IL-1β and TNF-α, leading to a systemic inflammatory cascade, renal failure, hypoglycemia, lactic acidosis and death. During the development of the parasites large increases of palmitic, myristic, stearic and oleic saturated acids and major decreases in polyunsaturated acids like DHA and EPA occur. These modifications must be a result of parasite metabolism. Plasmodium tries to obtain in the infected erythrocyte and in the food vacuole a fatty acid composition required to obtain maximal down-regulation of TNF-α output and protection against damaging effects. These favorable products are released into the medium during schizont rupture and merozoite release. F. Debierre-Grockiego, L Schofield, NAzzouz, Fatty Acids from Plasmodium falciparum Down-Regulate the Toxic Activity of Malaria Glycosylphosphatidylinositols INFECTION AND IMMUNITY, Oct. 2006, p. 5487–5496 Vol. 74, No. 10 All this is described in detail in an obsolete patent filed in 1992. Antonio Ferrante, Mt. Osmond; Alfred Poulos, Kensington Gardens; Lakshmi M. Kumaratilake Methods for treating malaria and other diseases US005604258A. Docosahexaenoic (DHA) acid, eicosapentaenoic (EPA), acid arachidonic acid (AA) and linoleic acid (LA) had a strong inhibitory effect on various Plasmodium falciparum isolates and in vivo on Plasmodium berghei in mice, at daily intraperitoneal doses of 10 µg. The antimalarial activity was concentration dependent. The monounsaturated oleic acid had a week effect, but none of the saturated fatty acids had any effect, even long chain ones. After oxidation PUFAs had a stronger effect. Antioxidants like Vit E, BHT, SOD, CAT reduced the antimalarial effect of PUFAs up to 70%. Importantly, the PUFAs showed no toxic effects in mice but, in fact, prevented malaria-induced anemia. Polyunsaturated fatty acids (PUFAs) lead to a 40% lower risk of type 2 diabetes. Salmerón J1, Hu FB, Manson JE, Stampfer MJ, Colditz GA, Rimm EB, Willett WC, Dietary fat intake and risk of type 2 diabetes in women. Am J Clin Nutr. 2001 Jun;73(6):1019-26. . In male Wistar rats, intake of fish oil containing DHA and EPA acids leads to increase in glucose utilization and insulin sensitivity. Breast-fed infants have a significantly higher percentage of DHA and lower plasma glucose concentrations than do formula fed-infants Baur LA, O'Connor J, Pan DA, Kriketos AD, Storlien LH. The fatty acid composition of skeletal muscle membrane phospholipid: its relationship with the type of feeding and plasma glucose levels in young children. Metabolism. 1998 Jan;47(1):106-12. Plasmodia also need cholesterol as food. After a malaria infection, the plasma concentration of cholesterol is lower. It is well known that PUFAs lower plasma cholesterol. Horrobin DF, Manku MS. How do polyunsaturated fatty acids lower plasma cholesterol levels? Lipids. Aug1983;18(8):558-62. In summary, PUFAs have a strong starving action on the malaria-causing pathogen, Plasmodium spp. PUFAs, prostaglandins and prophylaxis: There are many anecdotal reports on the prophylactic effect of Artemisia annua and this has been documented in several peer reviewed papers Patrick E. Ogwang, Jasper O. Ogwal, Simon Kasasa, Francis Ejobi, David Kabasa and Celestino Obua. Use of Artemisia annua L. Infusion for Malaria Prevention: Mode of Action and Benefits in a Ugandan Community. British Journal of Pharmaceutical Research 1(4): 124-132, 2011 Patrick E Ogwang, Jasper O Ogwal, Simon Kasasa, Deogratius Olila, Francis Ejobi, David Kabasa and Celestino Obua. Tropical Journal of Pharmaceutical Research June Trop J Pharm Res 2012; 13 (3): 445-453. Artemisia Annua L. Infusion Consumed Once a Week Reduces Risk of Multiple Episodes of Malaria: A Randomised Trial in a Ugandan Community But the mechanism of this action has not been elucidated. The prophylactic effect is not due to artemisinin and derivatives. If this was the case, it would have been broadcasted in all the media since years. Artemisinin is even immunodepressive. The advantage of Artemisia herbal polytherapy over artemisinin monotherapy in ACTs is significant. One hypothesis for this prophylactic effect is resting on the high concentration of fatty acids in medicinal plants. The prophylactic effect of PUFAs is well documented in the literature. Preliminary studies had indicated to a research team in Norway a suppressive influence of fish oils on rodent malaria Fevang P, Sääv H, Høstmark AT. Dietary fish oils and long-term malaria protection in mice. Lipids. 1995 May;30(5):437-41. In a subsequent work, for two or four week groups of weaning male mice were fed a standard laboratory diet or one of eight purified diets containing various amounts of fish oil (providing 6-21% of energy). The diets were prepared with and without vitamin E. After the two- or four-week feeding period, the mice were injected intraperitoneally with Plasmodium yoelii-infected erythrocytes. Six months after the primary infection (four months after discontinuing fish oil feeding), the surviving mice were again injected intraperitoneally with parasitized red blood cells (or even better--erythrocytes, erythrocytes are used elsewhere). Primary malaria infection was lethal in mice fed standard diet alone or with fish oil and vitamin E added. In contrast, feeding a fish oil-based diet without vitamin E improved survival to at least 70% if the mice had been fed these diets for four weeks. Protection against malaria did not seem to be related to the fish oil dose used. Regardless of the previous fish oil dose, all the mice surviving the primary infection survived the rechallenge infection with low parasitemia. A similar effect was found with menhaden-fish oil Levander OA, Ager AL Jr. Malarial parasites and antioxidant nutrients. Parasitology. 1993;107(suppl): S95–S106. Levander OA, Fontela R, Morris VC, Ager AL Jr. Protection against murine cerebral malaria by dietary-induced oxidative stress. J Parasitol. 1995 Feb;81(1):99-103. Feeding 20% menhaden-fish oil in a standard laboratory chow diet for 4 wk partially protected mice from the central nervous system consequences of infection with Plasmodium berghei. The effect of one of the PUFAs, arachidonic acid, ARA, on bilharzia has been extensively studied at the University of Cairo Rashika El Ridi, Marwa Aboueldahab, Hatem Tallima. In Vitro and In Vivo Activities of Arachidonic Acid against Schistosoma mansoni and Schistosoma haematobium Antimicrob. Agents Chemother. August 2010 vol. 54 no. 8 3383-3389 They have demonstrated that 5 nM ARA leads to irreversible killing of ex vivo 1-, 3-, 4-, 5- and 6- weeks old Schistosoma manzoni within 3 to 4 hours. This efficiency could be duplicated in vivo in mice indicating that using ARA in pure form or included in an infant formula consistently led to a 40 to 80% decrease in total worm burden. A possible link with malaria is that the addition of ARA to several Plasmodium falciparum strains grown in vitro led to a significant increase in prostaglandins PGD, PGE and PGF, molecules which are detrimental for the parasite. In the absence of ARA the production of prostaglandins was insignificant B. Kilunga Kubata, Naomi Eguchi, Yoshihiro Urade, Kouwa Yamashita, Toshihide Mitamura, Kumiko Tai, Osamu Hayaishi, Toshihiro Horii. Plasmodium falciparum Produces Prostaglandins that are Pyrogenic, Somnogenic, and Immunosuppressive Substances in Humans JEM 1998 Archive » 21 September » 188 (6): 1197 It is well known that prostaglandins are lipids mainly derived from arachidonic acid. Broughton KS, Rule DC, Ye Y, Zhang X, Driscoll M, Culver B. Dietary omega-3 fatty acids differentially influence ova release and ovarian cyclooxygenase-1 and cyclooxygenase-2 expression in rats. Nutr Res. 2009 Mar;29(3):197-205. doi: 10.1016/j.nutres.2009.01.007. Prostaglandins both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. But that does not clearly explain why they play a role in malaria. In children with cerebral malaria their production is impaired and this often leads to adverse outcomes, whereas elevated levels of PGE₂ in asymptomatic parasitemia suggest a potential role for PGs in protective immunity. Douglas J. Impaired Systemic Production of Prostaglandin E2 in Children with Cerebral Malaria. JID, 2005, 191, 1548-57). Already in 2000 it had been demonstrated in a study on Gabonese children with and without malaria that prostaglandins are important pro-inflammatory mediators of the host-immune response to infection. Weinberg, JB, Perkins, DJ, Granger, DL, Kremsner, PG, and Anstey, NM. "Nitric oxide as a nonprotein regulator of hematopoietic cell proliferation and differentiation-relationship to malarial anemia." BLOOD 96, no. 11 (November 16, 2000): 14B-14B The authors postulate that PGE₂ levels in healthy malaria-exposed children protects against malaria, while decreases in PGE₂ during acute malaria increase susceptibility to severe disease. This has been confirmed in Tanzanian children. The authors suggest that high levels of PGE₂ in children with asymptomatic parasitemia may contribute to the maintenance of malaria tolerance, which is the ability to tolerate circulating parasites without fever. In 1983 already it was claimed that PGE₂ derived from arachidonic acid plays a clear role in the regulation of cellular and humoral responses. Goodwin, J. S., and Ceuppens, J., 1983, Regulation of immune responses by prostaglandins, J. Clin. Immunol. 3:295-315 PGE₂ regulates macrophage derived TNF-α. These studies confirmed that this prostaglandin can regulate macrophage activity. PUFAs promote the phagocytosis of bacteria. Adolph S, Schoeniger A, Fuhrmann H, Schumann J. Unsaturated fatty acids as modulators of macrophage respiratory burst in the immune response against Rhodococcus equi and Pseudomonas aeruginosa. Free Radic Biol Med. 2012 Jun 1-15;52(11-12):2246-53 We have several anecdotal reports indicating that prophylaxis with Artemisia annua is more reliable in people leaving in endemic areas. It is well documented that phagocytosis is present at higher levels in hyperimmune people than in people suffering their first attack. Khusmith S, Druilhe P, Gentilini M (1982) Enhanced Plasmodium falciparum merozoite phagocytosis by monocytes from immune individuals. Infect Immun 35: 874–879 PUFA’s may enhance this immune effect. This is in line with the fact that in endemic areas the concentration of IL-1β, which is released by macrophages, is much higher in the blood of residents than in non-endemic areas Jean Langhorne, Francis M Ndungu, Anne-Marit Sponaas & Kevin Marsh Immunity to malaria: more questions than answers nature immunology volume 9 number 7 july 2008 Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) reduce outward potassium currents in ventricular myocytes. The efflux of potassium from infected erythrocytes is a critical issue in malaria. Hong-Xia Li, Ru-Xing Wang, Wen-Ping Jiang, Increasing DHA and EPA Concentrations Prolong Action Potential Durations and Reduce Transient Outward Potassium Currents in Rat Ventricular Myocytes. Lipids. 2011 46:163-70 Arachidonic acid has an effect on ion channels, stronger than oleic acid and much stronger than stearic acid. H Meves. Arachidonic acid and ion channels: an update. Br J Pharmacol. 2008 Sep;155(1):4-16. doi: 10.1038/bjp.2008.216. PGE₁ activates ATP-sensitive potassium channels, which induces vasorelaxation Eguchi S, Kawano T, Yinhua, Tanaka K, Yasui S, Mawatari K. Effects of prostaglandin E1 on vascular ATP-sensitive potassium channels. J Cardiovasc Pharmacol. 2007 Dec;50(6):686-91 Heme impairs PGE₂ formation. Patients with severe disease have lower concentrations than those with mild disease. Antimalarial treatments reverse the trend and PGE₂ see a 2 to 10 fold increase. This may be related to the crystallization of heme into hemozoin Bruno B. Andrade, Théo Arau´jo-Santos, Nıvea F. Luz, Heme Impairs Prostaglandin E2 and TGF-b Production. The Journal of Immunology, 2010, 185: 1196–1204. ARTAVOL from Uganda PGs are important soluble mediators involved in the immune response to invading pathogens and this may explain the strong prophylactic effect of ARTAVOL, a drug developed by Dr Patrick Ogwang from the University of Makerere and the Ministry of Health in Uganda. The powder contains lemongrass (Cymbopogon citratus), avocado (Persea americana) and Artemisia annua. Avocados contain 9% of fatty acids and 71 % of these are monounsaturated. The fatty acid of lemongrass is very rich in linoleic and oleic acid. Linoleic acid generates a strong PGE₂ production and oleic acid a weaker one. The prophylactic effect of lemongrass and neem is known and well described. M Farahna, S Bedri, S Khalid, Mustafa Idris, C. Pillai, and E A. Khalil Anti-plasmodial effects of Azadirachta indica in experimental cerebral malaria: Apoptosis of cerebellar Purkinje cells of mice as a marker. N Am J Med Sci. 2010 Nov; 2(11): 518–525. In ARTAVOLᴿ artemisinin has been removed from the Artemisia annua powder to avoid its immunodepressive effect. Artemisinin, dihydroartemisinin, arteanuin B, artemisinic acid strongly inhibit PG2 in vitro Xiaoxin X. Zhu Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis Pharmacological Reports Pharmacol Rep, Volume 2013; 65(2): 410–420 ISSN:1734-1140 Wan-Su Kim, Woo Jin Choi, Sunwoo Lee, Woo Joong Kim. Anti-inflammatory, Antioxidant and Antimicrobial Effects of Artemisinin Extracts from Artemisia annua L. Korean J Physiol Pharmacol. 2015 Jan; 19(1): 21–27. Uchechukwu P. Olumayokun A, Olajide, A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia. Bioorganic & Medicinal Chemistry, 2014 174726-34 The effect may be less pronounced in vivo where the metabolism of these peroxides is very rapid. And the complexity of prostaglandin generation and inhibition is large. It is known that scopoletin and phytosterols also interfer Awad AB, Toczek J, Fink CS (2004). Phytosterols decrease prostaglandin release in cultured P388D1/MAB macrophages. PLEFA 70:511–520. Acetaminophetamin (Paracetamol) inhibits the PGE₂ production. The hypocholesterolemic agent simvastatin activates the formation of AA from LA Risé P, Marangoni F, Galli C. Regulation of PUFA metabolism: pharmacological and toxicological aspects. Prostaglandins Leukot Essent Fatty Acids. 2002 Aug-Sep;67(2-3):85-9. Prostaglandins also alter the activity of the Na-K ATPase Webb RC, Lockette WE, Vanhoutte PM, Bohr DF. Monovalent ion specificity of the electrogenic sodium pump in vascular smooth muscle. Proc Soc Exp Biol Med. 1981 Mar;166(3):457-61 Host genetic factors and blood characteristics (sickle cell, O blood group, thalassemia, G6DP, PKD) certainly play a role. An effect Patrick Ogwang had noticed in his trials, was an increase in monocytes. This is in line with a thesis from Wake Forest University The role of Omega-3 fatty acids in determining monocyte and macrophage phenotypes, thesis, AL Brown, Wake Forest University, 2011. As fatty fish or fish oil is consumed in low quantities in the U.S. the author tried to determine whether the botanical oil from Echium plantagineum will alter macrophage phenotypes in a murine model. It had been noticed that echium oil reduced inflammation in a waysimilar to fish oil. Using flow cytometry it was found that PUFAs promote macrophage phenotype shifting from the more inflammatory M1 to a less inflammatory M2 phenotype from Wahke Forest University. PUFAs might also affect the invasion by sporozoites. A team from the University of Illinois (Project ILLU-888-918) identified a lipid fraction that inhibits Cryptosporidum parvum sporozoite invasion. Characterization of this lipid revealed it is a long-chain polyunsaturated fatty acid. Only PUFAs which are between 18-20 carbons long, have at least one double bond which is in the cis configuration, and have an unsubstituted carboxyl group are able to block sporozoite invasion. Preliminary data suggest these L-PUFAs inhibit invasion by blocking both sporozoite microneme secretion and gliding motility. Similar results were obtained for Eimeria tenella coccidiosis sporozoite invasion in vitro and in vivo. Crane, M. S. J.; McGaley, C. J., 1991: Eimeria tenella: inhibition of host cell invasion by phospholipase treatment of sporozoites. Experimental Parasitology 72(2): 219-222 The alteration affects the sporozoites and not the host cells. This inhibition of sporozoites by long chain fatty acids applies to many parasitic pathogens of the phylum Apicomplexa like Cryptosporidium parvum, Toxoplasma gondii, and Plasmodium gallinaceum. These parasites commonly infect a variety of vertebrate species and can produce life-threatening diseases, especially in the immunocompromised. This inhibition of sporozoite invasion could be related to the production of the potent bactericidal protein BPI by EPA and DHA. In a US patent Lewis Lambert, Anti-protozoan methods and materials US 20010029245 A1 it is claimed that BPI is also active against Leishmania, Trypanosoma, Plasmodium and Toxoplasma. Through its binding ability BPI derived from DHA and EPA may interfere with the binding of infectuous parasite forms to host cells. An in vivo study with mice, similar to the work of Patrick Ogwang has been made in Nigeria. They studied combinations of the plants Nauclea latifolia, Artocarpus altilis, Murraya koniigii, Enantia chlorantha. Adeleke Clement Adebajo 1,2,* , Samuel Akintunde Odediran 1, Fatimah Abosede Aliyu 1In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants Molecules 2014, 19(9), 13136-13146; doi:10.3390/molecules190913136 In a prophylactic model the ethanol-water extracts were administred using oral cannula, daily 3 days before infection with Plasmodium berghei, in the chemosuppressive model during 3 days immediately after infection and in the curative model after 3 days of infection during 5 days. For all the plants and/or their mixtures a significant effect on parasitemia was noticed, although not as strong as for the control drug chloroquine. The most striking result is obtained for survival time in the prophylactic approach : on the average a doubling of the survival time compared to much lower effects in the chemosuppressive and curative approaches. This indicates that the herbal treatment has a strong effect on the first steps of the plasmodial invasion and might be less effective on trophozoites ; it highlights the prophylactic and survival effect regular tea consumption. Another trial combining several medicinal plants under the tradename SCAT is described in a thesis from Pakistan. Afzal Ahmad, Clinical Study on Anti – Malarial Herbal Medicine, Ph.D. Thesis, 2005 Hamadard University Karachi The conclusion of a randomized clinical trial was that this herbal medicine is equivalent or even better than amodiaquine in reduction of parasitemia, but superior in avoiding side effects and relapses. Of considerable importance were the observations on gametocyte clearance with SCAT which showed a more rapid reduction in gametocyte numbers. Artemisia plants are rich in linolenic, linoleic acid and arachidonic acid but lack EPA and DHA present in fish oil. However alpha linolenic acid is easily converted in a healthy human into EPA and later into DHA. Linoleic acid is converted into arachidonic acid. This metabolism is slow and half-life of AA, DHA and EPA in human infants is longer than 4 days. For AA it is as long as 45 days. Joshua T. Green, Zhen Liu, and Richard P. Bazinet. Brain phospholipid arachidonic acid half-lives are not altered following 15 weeks of N-3 polyunsaturated fatty acid adequate or deprived dietJ Lipid Res. 2010 Mar; 51(3): 535–543. doi: 10.1194/jlr.M000786 A more elaborate study on DHA and EPA supplementation shows that these fatty acids are rapidly incorporated into plasma lipids. The DHA concentration in plasma plateaus at 350 mmol/ml. The half-life in plasma is 4 days and in whole body 100 days Plourde M, Chouinard-Watkins R, Rioux-Perreault C, Fortier M, Dang MT, Allard MJ, Cunnane SC. Kinetics of 13C-DHA before and during fish-oil supplementation in healthy older individuals. Am J Clin Nutr. 2014 Jul;100(1):105-12. doi: 10.3945/ajcn.113.074708. Plourde M, Chouinard-Watkins R, Vandal M, . Plasma incorporation, apparent retroconversion and beta-oxidation of 13C-docosahexaenoic acid in the elderly. Nutr Metab (Lond) 2011;8:5 Sung-Ha Hong, Ludmila Belayev, Nicolas Bazan, Docohexaeonic acid confers neuroprotection in experimental stroke. J Neurol Sci, 2014, 338, 135-141 In adipose tissue it even has a half-time of 680 as demonstrated by the use of radiactive PUFAs Ana Baylin , Mi Kyung Kim , Paula Tocco. Fasting Whole Blood as a Biomarker of Essential Fatty Acid Intake in Epidemiologic Studies: Comparison with Adipose Tissue and Plasma Am. J. Epidemiol. (15 August 2005) 162 (4): 373-381. doi: 10.1093/aje/kwi213 This explains why the consumption of a few cups of Artemisia infusion or capsules per week might generate a prophylactic effect. As during malaria infection, the concentration of unsaturated fatty acids rapidly declines, their presence and replenishment by the consumption of medicinal herbs may play an important role in prophylaxis and therapy.

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