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Artemisia plants, nematodes and hemozoin

January 10, 2017 - 19:34 -- Pierre Lutgen

Many Artemisia plants are called wormwood, because for thousands of years they have been used against worms. There have been some recent trials on animals, but most studies are in vitro.

No large scale, double blind, randomized clinical had been run on humans with this herbal medicine. A team of Congolese medical doctors run such a trial in 2016 in the province of Maniema Artemisia vs Praziquantel. The herbal infusion came out with a much higher efficiency against schistosomiasis and no side effects for the Artemisia arm. A total of 390 patients were involved. 97.7 % of the patients were cured in the Artemisia arm and only 71.4 in the Praziquantel arm. Praziquantel caused vomiting in 26.5% of the patients, abdominal pain in 18.5%, cephalalgy in 15.5%. Very impressive is the fact that the Artemisia treatment led to an unexpected almost complete absence of eggs in feces after 2 months.

These are breaking news which demonstrate for the first time the efficiency of Artemisia annua and Artemisia afra in humans. They confirm some preliminary results obtained in Senegal in 2014. 60 people of all ages, including pregnant women, were treated in an endemic area on the riverbanks of a river. Powdered leaves and twigs of Artemisia afra were administered during seven days as aqueous infusion or as powder mixed with food. After one month complete disappearance of worms was found for over 65% of the patients and probably more, because our partner was not equipped for distinguishing dead worms from living ones.

                                                                                                                                          In vitro trials

In the scientific literature even small in vivo trials with Artemisia plants against helminths in animals are difficult to find, most trials have been run with extracts in vitro. One of the first large scale in vitro trials in livestock were run by USDA against Fasciola hepatica, Echinostoma caproni and Schistosoma mansoni with six crude plant extracts. Artemisia annua, Artemisia absinthium and Asimia triloba showed the best effect. Others like Fumaria officinalis had no effect.

         J F S Ferreira, P Peaden, J Keiser, In vitro treamtocidal effects of crude alcoholic extracts of Artemisia annua, Artemisia absinthium, Asimina triloba and Fumaria officinalis. Parasitol Res 12 May 2011.

Further assays were continued in Moçambique with Artemisia annua against Haemonchus contortus with water, aqueous 0.1% sodium bicarbonate, dichlormethane and ethanol extracts. It is interesting to note that the sodium bicarbonate extract had by far the lowest LC99. Artemisinin 100 mg/kgBW treated sheep had a nonsignificant reduction of eggs per gram.

           A C Cala, J Ferreira, AC Chagas, J Gonzales PM Magalhaes. Anthelmintic activity of Artemisia annua extracts in vitro on gastrointestinal nematodes. Parasitol Res 2014 113, 2345-2353

In vitro trials in Nigeria showed that the survival time of Fasciola flukes was strongly dependant on concentration of Artemisia annua extracts.

           Owai PU, Umoren UE, Effects of leaf extract of Artemisia annua on Fasciola gigantica in cattle, J Agrul Biotech Ecology 2011, 4,3, 90-95

A more recent trial with Artemisia indica and Artemisia roxburghiana against gastrointestinal nematodes in small ruminants revealed that methanolic extracts were efficient in larval mortality assay and adult worm mortality assay.

          Khan S, Afshan K, Mirza B, Miller JE, Manan A, Anthelmintic properties of extracts from Artemisia plants against nematodes. Trop Biomed 2015 32(2) 257-68

                                                                                                                                         In vivo trials

Already in 1982 the anthelmintic efficacy of Artemisia herba alba had been documented against Haemonchus contortus in goats.

          Idris UE, Adam SE, Tartour G, The anthelmintic efficacy of Artemisia herba alba against Haemonchus contortus infection in goats: Natl Inst Anim Health (Tokyo) 1982, 22(3), 138-143

A trial with artesunate at the Swiss Tropical Institute against Fasciola hepatica gave dubious results. The egg and worm burden decreased during the treatment but 3 of the sheep died.

          Keiser J, Veneziano, Rinaldi L, Anthelmintic activity of artesunate against Fasciola hepatica in naturally infected sheep. Res Vet Sci 2009, Jun 4

Crude aqueous and methanolic extracts of Artemisia brevifolia shows in vitro and in vivo effects against nematodes.

          Z Iqbal, M Lateef, M Ashraf, A Jabbar, Anthelmintic activity of Artemisia brevifolia in sheep. J Ethnopharmacology, 2004, 93, 265-268

Similar effects were noticed for Artemisia maritima and Artemisia vestita.

          Irum S, Ahmed H, Mukthar M, Simsek S, Anthelmintic effects of Artemisia against Haemonchus contortus from sheep

Or Artemisia abrotanum

          M Amirmohammadi, S Khajoenia, M Bahmani, In vivo evaluation of antiparasitic effects of Artemisia abrotanum and Salvia officinalis extracts on Syphacia obelata,, Hymenolopsis nana parasites. Asian Pacif J Trop Disease, 2014, 4, Suppl 1, 250-254

Or Artemisia inculta in Egypt, against schistosomiasis.

          Lofty AA, Ghanem LY, Shenawy AM Assessment of the toxicity of Artemisia inculta extract on the bone marrow of mice infected by schistosomiasis. Arzneimitelforschung 2006, 56(2), 104-7

Or Artemisia cina

          Bashtar AR, Hassanein M, Al-Ghamdi, Studies on moniezasis of sheep. Parasitol Res, 2011, 108(1) 177-186.

Or Artemisia absinthium

          K.A Tariq, MZ Chishti, F Ahmad, Anthelmintic activity of Artemisia absinthium against ovine nematodes,Veter Parasit. 2009 160 1-2 83-88

A team from Poland finds that extracts from Artemisia annua show not only in vitro but also in vivo effects against amoebae in animals.

          M Derda, E Hadas, M Cholewinzi, Artemisia annua as a plant with potential use in the treatment of acanthamoebiasis. Parasitol Res 2016, January.

Artemisia annua is also efficient against Eimeria tenella in chickens

          L Dragan, A Györke, J ferreira, IA Pop. Effects ot Artemisia annua and Foeniculum vulgare on chickens highly infected wit Eimeria tenella, Acta Veter Scandinavica 2014 56:22

And Artemisia herba alba against Heterakis gallinarum.

          Shaker A Seddiek, Mohamed Ali, Hanem Khater, Anthelmintic activity of the white wormwood, Artemisia herba alba. J Mecinal Plants Res 2011, 5, 3946-57

 

                                                               Which molecules contribute to the anthelminthic properties of Artemisia

In the compendium where this chapter will be integrated, there are already three chapters which describe molecules which obviously contribute to the anthelmintic effect “Fish oil, arginine and nitric oxide”, “Arachidonic acid in Artemisia plants: precursors of prostagaldines” and “Santonin from Artemisia campestris” (also at www.malariaworld.org)

Artemether didn’t give the expected results

           L Pratico, B Mariani, E Bruneti, G Chichino, Failure of repeated treatment with praziquantel and artemether in four patients with acute schistomsomiasis. J of Travel Medicine 2014, 21, 133-136

And only moderate impact on the incidence of the disease and egg count in a previous large scale randomized clinical trial

           Utzinger J, N'Goran EK, N'Dri A, Lengeler C, Xiao S, Tanner M. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. Lancet. 2000 Apr 15;355(9212):1320-5.

A daisy from Bhutan has good nematocidal properties. Luteolin was found to be the most efficacious compound with an IC50 of 13,3 mg/L against Schistosoma mansoni in vitro and good in vivo results against Trichuris muri. It provoked major changes in the morphology and in the tegument of these worms.

           P Wangchuck, M Pearson, PR Glacomin, Compounds derived from the Bhutanese Daisy Ajanai nubigena demonstrate dual anthelmintic activity against Schistosoma manson and Trichuris murs, PLOS, Neglected Tropical Diseases August 4 2016. Doi 10,1371/journal.pntd

Aqueous extract of Artemisia annua and its components caffeic acid, chlorogenic acid, arteminsinin and artesunate were investigated against several nematodes. The aqueous extract had better potential than artesunate.

           D’Addabbo, T., Carbonara, T., Argentieri, M.P. Nematocidal potential of Artemisia annua and its main metabolites. Eur J Plant Pathol (2013) 137: 295. doi:10.1007/s10658-013-0240-5

Papaya carica has anthelmintic properties. This plant is rich in condensed tannins (proanthocyanidins). Several papers in the scientific literature describe anthelmintic effects of condensed tannins.

           Novobilsky A, Mueller-Harvey I, Thamsborg SM, Condensed tannins act against cattle nematodes. Vet Parasitol 2011, 182, 213-20

The tannin hypothesis has been verified against Ascaris suum in vitro

           AR Williams, C Fryganas, A Ramsay, Direct anthelminthic effects of condensed tannins from diverse plants sources against Ascaris suum. PLOS 2014, 9,5, e97053

The same effect against Ascaris suum was found for proanthocyanidins from cinnamon bark

           A Williams A Ramsay, T Hansen, Anthelmintic activity of A and B type proanthocyanidins derived from Cinnamum verum

Or from shea

          Ramsay A, Williams AR, Galloylated proanthocyanidins from shea (vitellaria paradoxa) meal have potent anthelmintic activity against Ascaris suum. Phytochemistry, 2016, 122, 146-53

The tannin hypothesis was to a large degree invalidated by the fact that peanut skins rich in tannins lack anthelmintic properties.

          CT McKown, MA Brown, EL Walker, Tannin rich peanut skins lack anthelmintic properties. Small Ruminant Research 2011. 96 2-3, 195-200

                                                                                               Linoleic and arachidonic acid

Fish oil is effective against helminthic diseases like trichinellosis. A reduction of 30,6 % of adult worms in Wistar rats was noticed in a fish oil group as compared to the standard diet group

          Gómez García V , Sanz Sampelayo MR , Fernández Navarro JR , Carmona López FD , Gil Extremera F , Rodríguez Osorio M. Polyunsaturated fatty acids and parasitism: effect of a diet supplemented with fish oil on the course of rat trichinellosis.Veterinary Parasitology [2003, 117(1-2):85-97]

Schistosomiasis trials were made with castor oil, praziquantel and fish oil. The oils, particularly castor oil, given by oral gavage for 7 days had the unexpected result to reduce cercarial penetration by 93%

           Salafsky B, Fusco AC , Li LH , Mueller J , Ellenberger B. Schistosoma mansoni: experimental chemoprophylaxis in mice using oral anti-penetration agents. Experimental Parasitology [1989, 69(3):263-271]

The effect of arachidonic acid on bilharzia has been extensively studied at the University of Cairo.

           Rashika El Ridi, Marwa Aboueldahab, Hatem Tallima, Mohamed Salah, Noha Mahana. In Vitro and In Vivo Activities of Arachidonic Acid against Schistosoma mansoni and Schistosoma haematobium. Antimicrob Agents Chemother. 2010 Aug; 54(8): 3383–3389. doi: 10.1128/AAC.00173-10

           Barakat R, Abou El-Ela NE, Sharaf S, El Sagheer O, Selim S, Tallima H, Bruins M, Hadley KB, El Ridi R. Efficacy and safety of arachidonic acid for treatment of school-age children in Schistosoma mansoni high-endemicity regions. Am J Trop Med Hyg. 2015 Apr;92(4):797-804. doi: 10.4269/ajtmh.14-0675.

They have demonstrated that 5 mM arachidonic acid 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 a series of 6 independent experiments in mice. Arachidonic acid in pure form or included in an infant formula consistently led to a 40 to 80% decrease in total worm burden. Arachidonic acid is already marketed for human use in the United States and Canada. Another clinical trial was run in Egypt on 66 schoolchildren comparing arachidonic acid with praziquantel. Arachidonic proved to be as efficacious as praziquantel: 78% and 85% cure rates respectively. Not a single child reported any adverse reactions during or after treatment after treatment with arachidonic acid. A majority of children treated with praziquantel reported headache, dizziness, abdominal pain, nausea and diarrhea.

            Sahar Selim, Ola El Sagheer, Azza El Amir, Rashida Barakat, Kevin Hadley, Maaike J. Bruins, and Rashika El Ridi. Efficacy and Safety of Arachidonic Acid for Treatment of Schistosoma mansoni-Infected Children in Menoufiya, Egypt. Am J Trop Med Hyg. 2014 Nov 5; 91(5): 973–981. doi: 10.4269/ajtmh.14-0328

Royal DSM has introduced an international patent claiming prevention and treatment of schistosomiasis with arachidonic acid combined with praziquantel (WO/2015/123480)

Arachidonic acid is present in eggs, meat, fish oil, but not in plants or vegetables, not even peanuts.  Except in Artemisia plants. 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.

            Kursat, M.; Emre, I.; Yılmaz, O.; Cıvelek, S.; Demır, E.; Turkoglu, I. Phytochemical contents of five Artemisia species. Notulae Scientia Biologicae 2015 Vol.7 No.4 pp.495-499 ref.47

The real surprise is that based on the total fatty acid content Artemisia armeniaca contains 6.47% arachidonic acid, A incana 7.79%, A tournefortiana 2.61%, A hausknechtii 7.44% A scoparia 3.17%. This is ten times higher than in meat, eggs or fish oil. And it is possibly related to the prophylactic and therapeutic properties of all Artemisia plants.

More important even is the presence of eicosadieonic acid 20:2 n-6 EDA. 10 % on the average in the five plants. EDA is also generating prostaglandins.

            Huang YS Huang WC Chuang LT. Eicosadienoic acid differentially modulates production of pro-inflammatory modulators in murine macrophages. Mol Cell Biochem, 2011 358 85-94.

The findings of Kursat op.cit, have been confirmed by a study from Taskkent. The hydrocarbon extract contains 17,2 mass% for the sum of 20.0. 22.0 amd 24.0 PUFAs. An extraordinary finding considering that they are absent in other plants.

            N T Ul’chenko, Z A Khushbaktova, N P Bekker A L Glushenkova. Lipids from flowers and leaves of Artemisia annua and their biological activity. Chemistry of Natural Compounds. 2005, 41, 3.

 

Arachidonic acid (AA or ARA) is an extremely important fatty acid involved in cell regulation. It is a polyunsaturated fatty acid (20:4n6) covalently bound in esterified form in membrane phospholipids of most body cells. Following irritation or injury, arachidonic acid is released and oxygenated by enzyme systems leading to the formation of an important group of inflammatory mediators, to the prostaglandins products (PGE₂) by the cyclooxygenase enzyme.

                                                                                                              The hemozoin evidence

Hemophagous, blood-feeding parasites use the hemoglobin of their host for energy supply. That is not only the case for Plasmodium, but also for most helminths, nematodes and trematodes. They have a common problem: get rid of the excess heme their digestion generates because this is a toxic substance at high concentrations. A key mechanism consists in the crystallization of heme into a pigment named hemozoin. And the same antimalarials like quinine and derivatives which have an effect in malaria also have an effect against schistosomiasis.

          Grove DI, A History of Human Helminthology, CABInternational, Wallingford UK, pp 848, 1990

           Xiao SH, Sun J2. Schistosoma hemozoin and its possible roles. Int J Parasitol. 2016 Dec 22. pii: S0020-7519(16)30273-9. doi: 10.1016/j.ijpara.2016.10.005.

Already in 2000 it had been shown that treatment of S. mansoni-infected mice with chloroquine led to remarkable decreases in Hz content and in the viability of the worms, as well as in parasitemia and deposition of eggs in mouse livers. The number of both male and female worms per mouse was drastically reduced. The most striking result, however, was the inhibition of deposition of eggs in mouse livers. Differences in the number of liver granulomas between control and chloroquine treated mice were observed after removal of the liver from the mice. This result has significant implications with regard to the treatment of the disease, since the eggs are the causative agents of the pathological deviations associated with schistosomiasis.

Amodiaquine had an effect similar to chloroquine but the impact of artemisinin was very moderate.

            Marcus F. Oliveira, Joana C. P. d'Avila, Antônio J. Tempone, Juliana B. R. Correâ Soares, Franklin D. Rumjanek, Antônio Ferreira-Pereira2, Sérgio T. Ferreira and Pedro L. Oliveira. Inhibition of heme aggregation by chloroquine reduces Schistosoma mansoni infection. J Infect Dis. (2004) 190 (4): 843-852. doi: 10.1086/422759

In 2010 the Swiss Tropical institute tested the efficacy of mefloquine and artesunate. Cure rates were only 21%, 25% against >95% for praziquantel. Secondary effects were noticed for all the children in the mefloquine arm: severe abdominal pain, vomiting, nausea, without talking about the possible long range neurological effects of mefloquine. Artesunate is known to increase ALT and AST, which is inappropriate in the case of a disease where liver and spleen are mostly affected.

            Jennifer Keiser, Nicaise A. N'Guessan, Koffi D. Adoubryn, Kigbafori D. Silué, Penelope Vounatsou, Christoph Hatz, Jürg Utzinger, and Eliezer K. N'Goran. Efficacy and Safety of Mefloquine, Artesunate, Mefloquine-Artesunate, and Praziquantel against Schistosoma haematobium: Randomized, Exploratory Open-Label Trial. Clin Infect Dis 2010,50, 1205-13

More recently a group from Brazil has demonstrated that heme crystallization into hemozoin within the Schistosomiasis mansoni gut is a major heme detoxification route and acting as a potential chemotherapeutical target. They investigated the effects of three antimalarial compounds: quinine , quinidine and quinacrine in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches. They observed that quinine treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. The overall significant reduction in several disease burden parameters by the quinine antimalarials indicates that interference with Hz formation represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat schistosomiasis.

            J Correa Soares, D Menenez, M Vanier-Santos, Interference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols. PLOS 2009, 3.7 e477

Let’s note that they found in their assays with Schistosoma parasites that artemisinin did not inhibit beta-hematin. But the research work at the University of Al Quds has found many other molecules, minerals and plants, mostly Artemisia, which inhibit beta-hematin. Their work on Plasmodium may have an important pay-off against bilharzia. And as malaria and bilharzia often go hand in hand in Africa the use of Artemisia infusions or leaf powder may have a significant impact on the overall health of children in Africa.