Jérôme Munyangi, Maniema, RDCongo, Lucile Cornet-Vernet, M4L France, Pierre Lutgen, IFBV-BELHERB, Luxembourg,
Since 9 years the association IFBV-BELHERB from Luxembourg has established a working relationship with African and South American universities, in close cooperation with other European research institutions. Several of these partners have run clinical trials with Artemisia annua tea. In all these trials a therapeutical effect of 95 % or higher was confirmed by the use over 7 days of whole leaf infusion , , ,  capsules or tablets. One of the surprising effects noticed in these trials was that that the artemisinin content had very little impact on the results. This lead us to make an analysis as complete as possible of all the constituents, organic and inorganic, in a large series of Artemisia annua samples from different origins . The effect of polysaccharides, amino acids, polyunsaturated fatty acids, pentacyclic triterpenes, cumarins, phytosterols and saponins has been neglected in the past . Several papers have shown that A. annua ingested as powdered leaves or in conjunction with fatty food significantly increases the artemisinin concentration in the blood and even overcomes resistance to artemisinin . It is well documented in the literature that A. afra or sieberi which contain little or no artemisinin are extensively used as antimalarials. They contain at least 5 molecules of the same antimalarial efficacy as artemisinin. Recent research from the Al Quds University has shown that aqueous infusions of several Artemisia species strongly inhibit beta-hematin, like chloroquine did . But the most important finding in several of the clinical trials, especially in Kenya and Uganda, was that people who drink one or two cups of Artemisia annua tea per week become immune against malaria . At Lubumbashi, RDCongo Dr C Kansango Tchandema has shown in 2014 that Artemisia annua and Artemisia afra raised CD4+[see2]. Anti-HIV properties of Artemisia afra have been documented by a team at the University of Leiden . Strong prophylactic results have been obtained with ARTAVOL, a mixture of herbs developed Dr Patrick Ogwang at the Ministry of Health . The produce does not contains Artemisia without artemisinin. In fact the antimalarial properties of Artemisia plants other than Artemisia annua are no surprise. The Chinese favoured Artemisia apiacea and the French in Algeria during 100 years protected their soldiers against malaria with Artemisia absinthium.
In 2015  a team of medical doctors in RDCongo, Jerome Munyangi and Michel Idumbo, have run randomized clinical trials on a large scale in the Maniema province with the participation of some 1000 malaria infected patients. The trials were run in conformity with the WHO procedures and compared Artemisia annua and Artemisia afra with ACTs (Coartem and ASAQ). For all the parameters tested herbal treatment was significantly better than ACTs: faster clearance for fever and parasitemia, absence of parasites and gametocytes as confirmed by PCR on day 28 for 99.5% of the Artemisia treatments and 79.5% only for the ACT treatments. A total absence of side effects was evident for the treatments with the plants, but for the 498 patients treated with ACTs, 210 suffered from diarrhea, and/or nausea, pruritus, hypoglycemia etc. The efficiency was equivalent for Artemisia annua and Artemisia afra [see2]. More important even is the observation for the total absence of gametocytes after 7 days treatment with the herb. A tremendous hope for malaria eradication. The results have been communicated to the local health authorities, and to the Ministries of Health and Research in the RDCongo who were supportive of these trials. The draft of a paper is almost ready and will be submitted to a peer reviewed scientific journal.
In parallel with the clinical trials against malaria, (see Breaking News Jan. 5 on http://www.malariaworld.org) the same team has completed another large scale randomized, double blind trial against schistosomiasis, Artemisia vs Praziquantel. The results confirm previous anecdotic results from several countries in Africa. Both arms in this trial had 400 infected patients. The treatment efficiency was 97 % in the Artemisia arm and 71% in the Praziquantel arm. No side effects were noticed in the Artemisia treatment. 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. Schistosomiasis kills 150 000 Africans per year and more than 70 000 000 are infected. A neglected disease in neglected, poor populations where the only existing drug, Praziquantel, loses efficiency year after year.
In 2016 clinical trials have been run against Tuberculosis and Buruli ulcer with Artemisia annua and Artemisia afra. Screening trials in 2015 had been promising and these recent large scale, randomized, double blind have resulted in an obvious therapeutic effect of these plants against Mycobacteria, not only tuberculosis but also Buruli ulcer. After three weeks of treatment the Ziehl stain assay is negative for alcohol-resistant bacteria. They will be published in the scientific literature. Most of us ignore that on Nov 3, 2015 a Convention was signed in Bali declaring the fight against the looming TB-Diabetes co-epidemic, one of the greatest global health challenges. An estimated two billion people, or one third of all people worldwide, live with a tuberculosis (TB) infection, of whom 9.6 million people develop active TB disease annually. TB is the leading cause of death worldwide due to a single infectious pathogen, responsible for 1.5 million human deaths in 2014, and 95 percent of human TB deaths occur in low- and middle-income countries. Diabetes mellitus is escalating worldwide. Clinical assays are planned to be run in the Katanga province of RDCongo with Artemisia plants against diabetes.
All these trials are run in compliance with the WHO protocol, full approval of the health authorities of the country and the province and encouragements of WHO-Afro.
1.Chougouo Kengne RD, Kouamouo J, Moyou Somo R, Penge On Okoko, (2009). Comparative Study of the Quality and Efficiency of Artemisinin Drug Based and Artemisia annua grown in Cameroun, MIM conference, Nairobi, Kenya, 2 Nov 2009, MIM 15225512
2. Kansango Tchandema C, Lutgen P. (2016) In Vivo Trial on the Therapeutic Effects of Encapsulated Artemisia annua and Artemisia afra. Global Journal for Research Analysis, 5(6), 228-234
3.Gebeyaw T, Vigzaw 1,, Tegbar V. (2010), Use of the Plant Artemisia annua as Natural Anti-Malarial Herb in Arbaminch Town, Ethiop J Health Biomed Sc 2(2), 75-81
4. Zime-Diawara H, Ganfon H, Gbaguidi F, Yemoa A (2015), The antimalarial action of aqueous and hydro alcoholic extracts of Artemisia annua L. cultivated in Benin, Journal of Chemical and Pharmaceutical Research, 7(8): 817-823
5.Chougouo Kengne RD (2010) Rapport de Stage. Mise au Point et Validation des Procédures analytiques pour la Détermination de certains Composés de la Plante Artemisia annua, Université des Montagnes, Cameroon, Laboratoire National de la Santé, Luxembourg
6.Onimus M, Carteron S, Lutgen P (2013) The Surprising Efficiency of Artemisia annua Powder Capsules. Med Aromat Plants 2: 125. doi:10.4172/2167-0412.1000125
7. Elfawal M, Towler M, Reich NG, Weathers P and Rich S (2014) Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin. http://www.pnas.org/cgi/doi/10.1073/pnas.1413127112
8. Akkawi M, Suhair J, Ogwang PE, Lutgen P (2014), Investigations of Artemisia annua and Artemisia sieberi water extracts, Medicinal & Aromatic Plants 3:1, ISSN: 2167-0412
9. Ogwang PE, Ogwal JO. Kasasa S. Deogratius O, Obua C (2012) Artemisia annua L. Infusion consumed once a Week reduces Risk of multiple Episodes of Malaria: A randomised tTrial in an Ugandan Community, Trop J Pharm res 13(3) 445-453
10.Van der Kooy F. Artemisia annua and its Anti-HIV Activity (2014) T. Aftab et al. (eds.), Artemisia annua – Pharmacology and Biotechnology, DOI: 10.1007/978-3-642-41027-7_14, Springer-Verlag Berlin Heidelberg
11 This document is an abstract intended for fast disclosure. It is based on personal communications. Figures, graphs and references of the clinical trials will be included in the peer reviewed scientific papers to be published in the coming months..
Jérôme Munyangi, Maniema, RDCongo, Lucile Cornet-Vernet, M4L France, Pierre Lutgen, IFBV-BELHERB, Luxembourg,
Most of us ignore that on Nov 3, 2015 a Convention was signed in Bali declaring the fight against the looming TB-Diabetes co-epidemic, one of the greatest global health challenges.
An estimated two billion people, or one third of all people worldwide, live with a tuberculosis (TB) infection, of whom 9.6 million people develop active TB disease annually. TB is the leading cause of death worldwide due to a single infectious pathogen, responsible for 1.5 million human deaths in 2014, and 95 percent of human TB deaths occur in low- and middle-income countries.
Diabetes mellitus is escalating worldwide. More than half of people with diabetes are unaware of their condition as they have never been tested, and 84% of all undiagnosed cases live in low and middle income countries,
People with diabetes are two-to-three times more likely to develop TB when compared to people without diabetes. The excess vulnerability to TB disease in people with diabetes is mainly related to altered immune response to TB infection as a consequence of high blood sugar due to undiagnosed or poorly controlled diabetes.
A Lancet study in 2009 had confirmed the convergence of the two epidemics (KE Dooley et al. Lancet Infect Dis. 2009. 91, 737-746). In 1934 already this link had been discovered in Boston MA (H Root, N Eng J Med 1934, 210,78). In a study in Egypt, which compared 119 patients with treatment failure to 119 controls, diabetes conferred a 3 times increased risk of treatment failure (AM Morsy et al., East Meditter Health J. 2003, 9, 689-701). Two retrospective cohort studies of patients with pulmonary tuberculosis in Maryland, USA, have shown a 6.5 times increased risk of death in diabetes patients (KK Oursler et al., Clin Infect Dis 2002, 34, 752-59). It appears also that tuberculosis may lead to diabetes in those not previously known to be diabetic (GP Nichols, Am Rev Tuberc 1957 76, 1016-30).
Our associations IFBV-BELHERB from Luxembourg and M4L from Paris are involved in clinical trials with African partners to study the in vivo effect of Artemisia annua and Artemisia afra on these diseases. Screening trials in 2015 had been promising and recent large scale, randomized, double blind have resulted in an obvious therapeutic effect of these plants against Mycobacteria, not only tuberculosis but also Buruli ulcer. After three weeks of treatment the Ziehl stain assay is negative for alcohol-resistant bacteria.
These trials were run in the province of Maniema, RDC Congo, in accordance with the WHO protocol and ethical approval of the local health authorities. They will be published in the scientific literature.
Jerome Munyangi, Lucile Cornet-Vernet, Pierre Lutgen
Ἓν οἶδα ὅτι οὐδὲν οἶδα
Our association IFBV-BELHERB has received numerous anecdotic reports on the prophylactic effects of Artemisia plants. This effect has been documented in scientific papers. Patrick Ogwang from Uganda (Ogwang PE, et al. Trop J Pharm Res. 2012;11:445–53) showed that an infusion of Artemisia annua consumed once weekly reduced the risk of Plasmodium falciparum episodes due to a yet unidentified constituent. All this is an important lead as classical antimalarial drugs like quinine (D.Shanks, Am Soc Trop Med Hyg, 2016, May), chloroquine (T Sahu et al., Frontiers in Microbiology, 2015, 1, 283), artemisinin are not prophylactic. They only act on the erythrocytic stage but have no impact on the liver stage invasion. They are just designed to kill the parasites in the erythrocytes, but they leave a bloody battlefield and a depressed immune system. Some even enhance the gametocytogenesis.
Many medicinal plants used against malaria in endemic areas are aimed to treat the acute symptoms of the disease such as fevers and their action is limited to these symptoms. In some endemic areas of the Brazilian Amazon region one medicinal plant seems to be an exception: Ampelozyziphus amazonicus, localla named “Indian beer” used to prevent the disease when taken daily as a cold suspension of powdered dried roots (VF Andrade-Neto et al., Int J Parasitology, 2008, 38, 1505-11). In infections induced by sporozoites, chickens treated with extracts of this plant were partially protected against Plasmodium gallinaceum. Some animals did not become infected, whereas others had a delayed prepatent period, lower parasitemia and a reduction in mortality. A delay in the time until parasites establish blood stage infection is not a minor effect. It reduces the risk of severe and cerebral malaria.
In a previous document published on http://www.malariaworld.org “Pentacyclic triterpenes in antimalarial plants, a new paradigm” we alerted to the important role these acids play in malaria control. And indeed Ampelozyziphus amazonicus is very rich in pentacyclic triterpenes, mainly betulinic acid (D do Carmo et al., Pharmacognosy Magazine, 2015, 11, 244-250). Betulinic acid, maslinic acid, oleanolic acid, ursolic acid and others seem thus to be responsible for the prophylactic activity of these plants. But that does not explain why.
Another good example for the antimalarial and prophylactic effect is Phyllantus amarus. This plant is well known for these properties in Ghana (R Appiah-Opong et al., Ghana Medical Journal, 2011, 45, 143-146), in Burkina Faso (M Traore et al., Phytother Res. 2008. 22, 550-1, in Nigeria, RDCongo (L Tona aet al., J Ethnopharmacol. 2004, 93, 27-32), but also in China, India, Brazil. The aqueous extract shows suppressive and curative properties similar to standard antimalarials like chloroquine, or artesunate, but it also shows prophylactic properties by delaying the onset of infection (T Ajala et al., Asian Pacific J Trop Med 2011). The plant is very rich in pentacyclic triterpenes.
DO PENTACYCLIC TRITERPENES ACT AS HERBICIDES AGAINST THE PLASMODIUM APICOPLAST
The apicoplast is a plastid organelle, homologous to chloroplasts of plants or algae, that is found in apicomplexan parasites like Plasmodium or Toxoplasma. In hindsight it seems incredible that such an organelle with a nonmammalian metabolism could so long have concealed its identity in parasites that have received as much scientific attention as Plasmodium (RF Waller et al., Curr Issues Mol Biol 7, 2005, 57-80). It is now recognized that this large group of parasites had a photosynthetic ancestry and were converted into parasitism early in the evalution of animals. Apicoplast function is necessary for both intraerythrocytic and intrahepatic development. Recently it was found that the apicoplast is also present in the gametocytogenesis, in the sexual stage of Plasmodium falciparum. But only the female macrogametes have an apicoplast, the male microgametes don’t (N Okamoto et al., Eukaryot Cell 8(1) 2009, 128-132).
Attempts have been made to find antimalarials which selectively attack the apicoplast. Several antibiotics are known to interfer with this organelle. They do not kill parasites in the first generation, but the progeny of drug-treated parasites suffer a delayed death, probably because they lose their apicoplast and the second generation of merozoites is unable to penetrate erythrocytes. Antibiotic treatment specifically inhibits the biogenesis and inheritance of the apicoplast in Plasmodium falciparum liverstage, resulting in continuous liver stage maturation but subsequent failure to establish blood-stage infection. This process of maturation of numerous merozoites in the liver induces potent immune protection for subsequent infections. This prophylactic protection obtained by several antibiotics was demonstrated to be exceptionally robust (J Friesen et al., http://www.ScienceTranslationalMedicine.org, 2010, 2).
Many herbicides also have an activity against the malaria protozoan (S O Duke, Weed Science, 58, 2010, 334-339). Herbicides interfer with plant cells by interrupting mitosis and the formation of multinucleated cells. A good example is the action of herbicides from the nitroanilin family (trifluralin, oryzalin). They have a strong action on Plasmodium falciparum. The herbicide amiprophosmethyl also has antimalarial activity and a significant action on schizogony, i.e. the formation of multinucleated parasites. A more surprising example is the effect of the well known glyphosate on several apicomplexa like Plasmodium falciparum, Toxoplasma gondii (F Roberts et al., Nature 393, 801-805, 1998).
Several herbicides including those of the cyclohexanedione family act by perturbing the apicoplast fatty acid biosynthesis (C Goodman et al., Int J Parasitol. 2014, 44, 285-289). This synthesis is dispensable in blood stages of human and rodent malaria, but vital for for the liver stage.
Artemisia annua has strong allelopathic properties as was documented by Mediplant in Switzerland. In other words the plant becomes invasive and inhibits the growth of other plants or cash crop on fields where Artemisia has been planted for the extraction of artemisinin. A recent paper from Iran (MH Bijeh Keshhavarzi et al, J Biol & Envir Sci. Nov 2014) describes the allelopathic effects of Artemisia annua on lettuce Lactuca sativa. The aqueous extract on an outside plot significantly reduced germination percentage and rate, fresh and dry weight. Another paper (Seyed Mohsen et al., Annals of Biological Research, 2011, 2-6, 687-69) describes the allelopathic effect of Artemisia annua aqueous extracts on vegetables and plants like Portulaca olearcea (pursley), Chenopodium album (goose-foot), Avena ludoviciana (oat), Plantago ovata (plantain). For the latter the effects are noticeable on germination percentage, germination rate, plumule length, radicle length, wet weight, dry weight. A Chinese paper (Shen He et al., Ying Yong Sheng Tai Xue Bao. 2005 Apr;16(4):740-3) had previously studied the allelopathy of different plants. Artemisia annua affected the seedling height and fresh weight of radish, cucumber, wheat and maize around 50%.
But the allelopathy of Artemisia remains a controversial issue. Although in vitro trials on seed germination of various plants show an impact of artemisinin and flavonoids, this remains far from field effects noticed and may only offer a partial explanation, Artemisinin and flavonoids are hardly soluble in water and rapidly degraded in the soil.
A recent paper offers an explanation which is very attractive proposing the role of pentacyclic triterpenoids in the allelopathic effects of Alstonia scholaris. (Wang CM1, J Chem Ecol. 2014 Jan;40(1):90-8). Alstonia scholaris is a tropical evergreen tree native to South and Southeast Asia. Alstonia forests frequently lack understory species. However, potential mechanisms, particularly the allelochemicals involved remain unclear. They identified allelochemicals of A. scholaris, and clarified the role of allelopathic substances from A. scholaris in interactions with neighboring plants and showed that the allelochemicals from leaves, litter, and soil from A. scholaris were identified as pentacyclic triterpenoids, including betulinic acid, oleanolic acid, and ursolic acid. In the field, ursolic acid accumulated abundantly in the soil in A. scholaris forests, and suppressed weed growth during summer and winter. A. scholaris pentacyclic triterpenoids influence the growth of neighboring weeds by inhibiting seed germination, radicle growth, and functioning of the photosystem.
These molecules are stable in powder form and in water for months (P Puttarak et al., Natural Product Sciences, 2016, 22, 1-20)
If the pentacyclic triterpenes have an allelopathic, herbicidal effect, this offers a completely new hypothesis and opportunity for destroying the malaria parasite in all its forms, from hepatocytes to gametocytes.
THE SKIN AS BARRIER
As the primary interface between the body and the outside environment, the skin protects the host against invading organisms.
It has always been assumed that sporozoites rapidly exit the injection site and enter the blood circulation. But it was demonstrated by PCR that the majority of the infective sporozoites remain in the skin for hours (L M Yamauchi et al., Cellular Microbiology, 2007, 9, 1215-22). The same authors had shown in preliminary studies no decrease in the sporozoite loads in the skin up to 3h. These findings imply that there is ample time for host and parasite to interact at the inoculation site and that tailored treatments of the skin might inhibit the survival of the sporozoites before they enter the bloodstream. At 37°C the time required for sporozoite penetration in hepatoma cells is 3 hours (VF Andrade-Neto op.cit.). Malaria-specific CD8⁺ T cells are primed in the skin draining lymphs (S Chakravarty et al., Nat Med 2007, 13, 1035-1041). A significant reduction in anti-sporozoite CD8⁺T cell response was observed in animals that had their draining lymph nodes removed prior to sporozoite infection. Pentacyclic triterpenes could play a role. Topical application of ursolic and maslinic acid for example significantly reduces epidermal inflammation, NF-κB, Cox-2 and skin tumor proliferation (Jiyoon Cho et al., Oncotarget, 6-36, 39292-305).
The high concentration of pentacyclic triterpenes in the skin of fruits or barks of trees evidently has the function to repel parasites and molds and to prevent their entry into the fruit or plant. Betulinic acid acts as an antifeedant (SG Jagadesh et al., J Agric Food Chem. 1998, 46, 2297-99). It affects the growth of larvae and pupae (V Lingampally et al., Asian J Plant Sc and Res. 2012, 2, 198-206).
Unlike many other microbial organisms that utilize the phagocytic properties of their host for invasion, sporozoites actively invade hepatocytes. They even pass through several hepatocytes prior to the final hepatocyte in which they develop. The reason for this process is not well understood; it is likely that the sporozoites choose the best environment for their differentiation into merozoites. Sporozoites have specialized secreting organelles in the apical region which play a central role in host cell invasion. The migration through several hepatocytes increases sporozoite competency for the formation of these apical organelles.
To survive and develop in the parasitophorous vacuole inside the hepatocyte the parasite has developed several strategies including depletion of CD-8 lymphocytes and suppression of NF-κB to prevent cell death. The circumsporozoite protein (CSP) plays a key role in this inhibition of NF-κB.
Memory CD8⁺T cell populations residing in the liver provide the first line of defence against naïve infections, but more even in subsequent infections and are the key players of the recall response. Any immune strengthening approach, including vaccines, requires the generation of a robust, stable memory population. In particular, CD4⁺cell help was shown to be required for CD8⁺memory cell responses against malaria (She-Wak Tse et al., Mem Inst Oswaldo Cruz 2011, 106, 172-178). CD4⁺helper T cells are critical orchestrators of immune responses. CD4⁺T cells decrease the threshold required for protective immunity and this immunity may last for months (NW Schmidt et al., PNAS, 2008, 105, 14017-22).
It was shown that oleanolic acid upregulates the CD4⁺and CD8⁺populations (J Wang et al., International Immunopharmacology 2012, 14-4). It was also found that betulinic acid increased the total number of thimocytes, splenocytes, lymphocytes. It is a potential biological response modifier and may strengthen the immune response of its host (Y Jine Polish J Veterinary Sc. 2012, 15, 305-13). This is in line with our findings in Katanga where we confirmed that administration of capsules containing Artemisia leaf powder raised the CD4⁺ (Constant Kansongo Tchandema, personal communication). This strengthening of the immune system by Artemisia plants may also be related to the pentacyclic triterpenes they contain.
Delayed apoptosis of infected hepacytes is another strategy of defence of the sporozoites. Blocking apoptosis allows the parasite to complete its full cycle and the merozoite burden is strongly enhanced. It fully exploits host cell resources and ultimately produces tens of thousands of merozoites which are released from the hepatocyte. Sensitizing the infected hepatocyte to apoptosis may substantially reduce parasite burden. Recent evidence suggests that Plasmodium infected hepatocytes are similar to cancer cells. The authors demonstrate that the anticancer drug obatoclax reduced the number of infected hepatocytes by > 70%, but had limited effect on uninfected cells (A Kaushansky et al., Cell Death and Disease, 4. E762). Many pentacyclic triterpenes, like betulinic acid, are used in cancer treatment. It seems worthwile to study their effect in malaria infection.
Several antibiotics also have an effect during the hepatocytic stage. Others, including tetracyclines and clindamycin used for the treatment of malaria, have little action on the pre-erythrocytic stages.
An extensive study has been made on the antibiotic thiostrepton and the effects of this drug on life-cycle stages of the malaria parasite in vivo. Preincubation of mature infective sporozoites with thiostrepton has no observable effect on their infectivity. Sporozoite infection both by mosquito bite and sporozoite injection was prevented by pretreatment of mice with thiostrepton. Thiostrepton eliminates infection with erythrocytic forms of Plasmodium berghei in mice. (M Sullivan et al., Mol Biochem Parasit 2000 109, 17-23).
After its release from the hepatocyte the merozoites penetrate the erythrocytes very rapidly. Parasite entry into erythrocytes is a complex, dynamic process. The invading merozoite orients its apical end toward the junction of invasion. Invagination of the erythrocyte bilayer then results in engulfment of the parasite. Merozoites without their apicoplast are unable to penetrate red blood cells.
A study of the Walter Reed Army Institute already in 1992 found that the herbicide Trifluralin showed strong anti-malarial effects not only on Plasmodium falciparum in cultures, but also transmission blocking by inhibiting gametocyte maturation and viability (J Nath et al., 19th Army Science Conference, 1994).
Thiostrepton (op.cit) treatment of infected mice reduces transmission of parasites by more than ten-fold, indicating that the plastid has a role in sexual development of the parasite. These results also indicate that the plastid function is accessible to drug action in vivo and important to the development of both sexual and asexual forms of the parasite.
Supply of the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the essential metabolic function of the apicoplast for isoprenoid biosynthesis, particularly during gametocytogenesis. When IPP supplementation was removed early in gametocytogenesis, developmental defects were observed, supporting the essential role of isoprenoids for normal gametocytogenesis. Furthermore, mosquitoes infected with gametocytes lacking the apicoplast developed fewer and smaller oocysts that failed to produce sporozoites. This finding further supports the essential role of the apicoplast in establishing a successful infection in the mosquito vector (J Wiley et al., Eukaryotic Cell 2015, 14, 128-133)
Was the Nobel prize for artemisinin a fatal error?
April 2, 2016 – 06:26 — Irene Teis
In 2015 a Nobel Price was attributed to Youyou Tu, almost 50 years after a report describing artemisinin’s structure, pharmacology, and efficacy had been published in 1979 by the “Qinghaosu Anti-Malarial Coordinating Research Group,” where she was a member of. Mr Huang Shuze, Deputy Minister of Health, stated in his 1981 summary report “Project 523 mobilized multiple departments ; thirty scientific research units and medical schools in 1975”.
WHO for decades hesitated in considering this traditional medicine approach. Only at the end of the nineties, when chloroquine’s resistance became overwhelming did first clinical trials take place. But artemisinin was not water soluble, hardly bioavailable, metabolized very rapidly and gave premature signs of resistance. WHO then prescribed in 1998 extremely high doses up to 1 200 mg of artemisinine for a person of 60 kg on the first day of treatment (WHO/MAL/98.1086) , at the verge of severe neurotoxicty and hepatoxicity.
A RECENT PAPER RINGS AN ALARM BELL. Plasmodium chabaudi malaria parasites through a step-wise increase in artesunate dose evolve extremely rapidly slow clearance rates. These slower clearance rates provide fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. Removal of only the susceptible parasites by artesunate treatment led to substantial increases in the densities of resistant parasites (LC Pollit et al., PloS Pathogens 2014, 10,4, e1004019). The traditional view has been that aggressive chemotherapy , involving high doses applied for sufficiently long time to eliminate parasites, best minimizes the evolution of resistance. For this reason WHO in several statements has condemned the use of Artemisia annua herbal treatment because of low artemisinin concentrations in the infusions. But numerous clinical trials, small and large, demonstrated that Artemisia annua and Artemisia afra infusion or powdered leaves reduce parasitaemia much more efficiently than ACTs and eliminate all gametocytes (see Breaking News for clinical trials with Artemisia plants, on http://www.malariaworld.org).
Previous work using the anti-malarial pyrimethamine has shown that removing susceptible competitors through drug treatment can lead to dramatic increases in the density of resistant parasites.
Resistance can also be affected by the dormancy effect (A. Codd et al., Malaria Journal, 10:56, 2011). One of the side effects of the higher doses of artemisinin is this effect induced in plasmodium. The parasite encapsulates itself against the aggressive peroxide artesunate and reawakens at the end of the treatment. The same effect is called quiescence by a French research team (B. Witkowski et al., Antimicrob Agents Chemother. Doi:10.1128/AAC.01636-09). Under a very high dose of artesunate, a Plasmodium falciparum ring-stage sub-population persists in culture and continues its cycle of development normally after drug removal. This may be one of the causes of resistance.
During the Ebola crisis in West Africa. Medecins sans Frontières administered 1.5 million treatments of artesunate-amodiaquine in Sierra Leone in a mass drug administration campaign. This is the largest-ever mass distribution of antimalarials. It is impossible to find any results on PubMed? Was it a failure with dramatic consequences, deathtoll or resurgence?
MSF-Coarsucam clinical trial with horrendous death toll
Submitted by Marc Vanacker (not verified) on April 4, 2016 – 17:46
There is indeed a peer reviewed paper (E Guignoux et al., NEJM, 2016 ;374 :23-32) which refers to the MDA clinical trials made by Médecins sans Frontières with artesunate-amodiaquine during the 2014 Ebola crisis. Not in Sierra Leone but in Liberia. Not with 1 500 000 patients but with 382 (three hundred eighty two).
As per Table 2 there were three branches in the trial : 194 patients for Coartem, 71 for Coarsucam and 63 with no antimalarial drug prescription.
In the Coartem group 125 (64.4%) died, in the Coarsucam group 36 (50.7%) and in the no drug group 41 (65.1%).
It is surprising that the total number of patients quoted in the abstract : 382, does not match the total number of patients in table 1 : 278, neither in table 2: 328, nor table 3: 282 nor in table 4: 295. This needs to be clarified as the statistics become dubious
Whatever, the authors make the dazzling claim that the 71 patients who were prescribed artesunate-amodiaquine had a lower risk of death than did patients who were prescribed artemether-lumefantrine.
A pyrrhic victory for Médecins sans Frontières on a bloody battlefield. Sanofi-Aventis will evidently continue to subsidize them. Amodiaquine is banned in France and artesunate-amodiaquine will now probably become available in French pharmacies
March 23, 2016 – 16:23 — Pierre Lutgen email@example.com
A very recent paper of a South African research team shows that among 8 medicinal plants Artemisia afra has the lowest IC50 for impairing the development of late stage gametocytes (P Moyo et al., J of Ethnopharmacology, acceopted 15 March). A very important finding as not many plants have such a significant gametocytocidal effect.
It confirms the in vivo results obtained end of 2015 in a large scale, double blind randomized clinical trials in Maniema, RDCongo (see Breaking news from clinical trials with Artemisia plants) where Artemisia afra was one of the branches of the test. Artemisia herbal tea completely eliminated gametocytes but they were still present on day 28 in 10% of those treated with Coartem In 2013 already Dr Constant Kansongo in Katanga had found in a trial with 44 Plasmodium falciparum infected patients that after 7 days of treatment with 20 gr of capsules containing A afra powder the gametocytes had completely disappeared, except for one patient. Artemisia afra does not contain any artemisinin. The best explanation available is the high arginine content of Artemisia plants (see « Arginine, a deadly weapon against gametocytes » on malariaworld.org). Frank van der Kooy at the University of Leiden found that Artemisia afra has anti-HIV properties stronger than Artemisia annua.
The situation is completely different for artemisinin derivatives and ACTs, it is even alarming. A paper from Mali published in February clearly shows it (AA Djimbe et al., Parasite, 2016. 23, 3). Artesunate does not clear mature gametocytes during oral artesunate treatment and does not prevent the appearance of new gametocytes. The same recrudescence with oral artemisinin monotherapy had already been observed in Vietnam in 2001 (PT Giao et al., Am J Trop Med Hyg, 2001 65 690-695). The conclusion of the authors was that artemisinin monotherapy may offer rapid recovery and fast parasite clearance, but recrudescence is frequent. For up to 20 percent of the cases on day 28, although gametocytes had completely disappeared on day 7. Extending the duration of the monotherapy from 5 to 7 days did not reduce recrudescence. A study from Kenya had also found that gametocyte carriage was much lower on day 14 than on day 28 and 42 for artemether lumefantrine, but not for dihydroartemisinin-piperaquine (P Sawa et al., J Infect Dis, 2013, 207, 1637-45). It is well known that artemisinin drugs are gametocytocidal for immature, but not mature gametocytes (GO Ghotosho et al., Mem Inst Oswaldo Cruz 2011, 106 no5). A paper of the Swiss Tropical and Public Health Institute (BJ Huho et al., Malaria Journal, 2012 11:118) comes to the conclusion that in high perennial transmission settings case management with ACT may have little impact on overall infectiousness of the human population. They even found in their study, that the most direct indicator of human-to-mosquito transmission, namely oocyst prevalence was substantially higher after ACT introduction. A study from Burkina Faso found in a recheck 12 months after a clinical trial with ACTs that the number of symptomatic malaria episodes was even slightly higher in the ACT arm than in the control arm and that after several treatments the prevalence of gametocyte carriers was the same in both arms (AB Tiono et al.,Malaria Journal 2013, 12:79). Another study found that ACT did not significantly reduce the proportion of infectious children. Submicroscopic gametocytaemia is common after treatment and contributes considerably to mosquito infection. (JT Bousema J Infect Dis., 2006, 193, 1151-59). Because of the short half-life of artemisinin and because high doses induce dormancy in the asexual parasite, asexual forms, mostly rings, remaining after completion of ACT may develop into mature gametocytes 7-15 days later. Some patients have the first appearance of gametocytemia 4-8/day after completion of a 3 day-ACT. (Wilairatana P, et al.,Southeast Asian J Trop Med Public Health. 2010 Nov;41(6):1306-11). What worries the authors of the study from Mali is not only that similar results had been found in a study in 2002-2004, but the fact that baseline gametocyte carriage was significantly higher 6 years after deployment of ACTs in this setting. If artemisinin derivatives really enhance recrudescence and gametocyte carriage, this is indeed alarming. It would mean that ACTs will not eradicate malaria but enhance it in the long run.
When IFBV-BELHERB had raised this concern with WHO Geneva and ITG Antwerp the blunt answer received from one of the experts was: “Your arguments do not make any sense from a public health point of view ».
Artemisia afra is growing wild from The Cape to Addis Abeba.
No further need to import Nobel prize validated pharmaceutical drugs from China or Europe
Malaria, folates and PABA
April 13, 2016 – 17:38 — Pierre Lutgen
Folates combine three molecules : pretidine & para-aminobenzoic acid (PABA) & glutamate. They were discovered around 1940 and first isolated from spinach leaves. The term folate is derived from the latin word folium.
The malaria parasite has a unique feature of being able to salvage exogenous folate derivatives and/or synthesize them de novo. Due to its high rate of replication, the parasite has a high demand for folates. Folate metabolism is the target of several antimalarials.
Food fortified with folic acid has been available for consumption in North America for over two decades. African countries are now embracing this concept; however, because folate promotes malaria parasite division, as it does in cancer cells, there is a possibility of malaria exacerbation if folate intake is increased. (Nzila A1Food Nutr Bull. 2016 Mar 4. pii: 0379572116634511).
The detrimental role of PABA (para-amino benzoic acid) on malaria has already been described 60 years ago (F Hawking, British Medical Journal, 1954, Feb, 425-429). Rats fed on a milk diet were insusceptible to infection with Plasmodium berghei. Milk does not contain PABA or only traces. This insusceptibility was reversed by the addition of PABA or folic acid. The same experiences were repeated on monkeys and gave the same results. It is likely that the relative immunity to malaria shown by infants in many parts of the tropics may be due to a deficiency of PABA in their mother’s milk.
In 1991 it was found that feeding wistar albino rats on low protein and low energy diet caused suppression of P berghei parasitaemia. When PABA was added to the diet parasitaemia re-elevated (A Bhatia et al Indian J Malariol 1991, 28 237-42). The same effect had already been inadvertely noticed in in vitro trials (CF Gilks et al., Parasitology, 1989 89 175-177).
Another research team showed that dietary folate deficiency protects primates against malaria (KC Das et al., Blood, 1992, 80-281). Blood infected with Plasmodium cynomolgi was injected into-folate deficient animals and folate-replete control animal. All control animals developed malaria and several died.
A more recent study extensively studies the effect of dietary PABA on murine Plasmodium yoelii infection (GA Kiczska et al., JID, 2003, 188, 1776-81). Plasmodium species, unlike humans, can utilize PABA for de novo generation of folate. The authors show that, despite the presence of biosynthetioc machinery to synthesize PABA, Plasmodium yoelii, a rodent malaria species, requires exogenous dietary PABA for survival. Mice fed low-PABA-diets do not die from lethal doses of P.yoelii. The initiation of a PABA-deficient diet after P.yoelii infection is established, leads to the clearance of parasites and subsequent resistance to infection by P. yoelii. An intact immune system is not necessary for protection given that mice with severe combined immunodeficiency were also protected by PABA-deficient diet.
In a trial made in The Gambia involving 600 children with uncomplicated falciparum malaria, among children who received the antifolate sulfadoxine-pyrimethamine, the treatment failure rate was significantly higher in those given folic acid than those given placebo (MB van Hensbroek et al., Trans R Soc Prop Med Hyg 1995,89, 672-6). And the authors suggest that the WHO recommendation of universal folic acid supplementation should exclude children in areas of high prevalence.
In a randomized, double blind prophylactic trial in Zanzibar the authors had to conclude that the routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. (Sazawal S et al., Lancet. 2006 28;367(9507):302.
Another more recent study confirmed that high dietary folate in mice alters immune response and reduces survival after malarial infection (DN. Meadows, et al., PLOS One 2015 Nov 24. doi: 10.1371/journal.pone.0143738)
In case of malaria infection diet should be low in folates or PABA. Swamping Africa with multiple micronutrient powders (MNPs)from Switzerland, , nutraceuticals from the US, “compléments alimentaires” from France, all containing folates, is questionable. The folic acid fortified milk market is booming. Business on the verge of crime.
A plant which could be detrimental during malaria infection is Moringa oleifera. The average folate in vegetables is 40 microg/100g but in Moringa oleifera it goes up to 540 microg/100g DW (K Witt Echo Research Note No 1, 2012). Moringa is rich in glutamic acid – 5 times more than Artemisia- and para-aminobenzoic acid (PABA), two of the building blocks of folate (G Magnani et al., Biochem J, 2013455, 149-155). PABA is a major constituent in Moringa oleifera and soya (L Mbanga et al., Adv Biochem & Biotechnol., 2015, 1, 1-13). It was never detected in Artemisia annua. A recent paper studied the relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model. The bioavailability of folate from dried leaves was 81.9%, which is much higher than the values of 50% known for other plants (Saini RK et al., J Food Sci Technol. 2016 ;53:511-20).
Several recent large scale trials in RDCongo (see “Breaking news from clinical trials with Artemisia plants, malariaworld.org) have shown that Artemisia annua and Artemisia afra completely eliminate gametocytes from malaria infected patients.
This is very encouraging for those who really want to eradicate malaria.
But another research team found that PABA administered to gametocyte-carrying mice increased the number of oocysts in mosquitoes fed on them (W Peters Ann Trop Med Parasitol 1980, 74, 275-82). High PABA content in the diet leads to the selection of drug resistant parasites in mice. A higher yield of resistance was related to the higher parasitaemia generated by PABA (B Merkli et al., Exp Parasit 1983 55, 372-6).
That is worrying. We are supposed to know. But the malaria experts from WHO and Tropical Medicine Institutes close their eyes on it.
Lors de la conférence du 19 mai 2014 à l’Université du Nebraska qui portait sur le SIDA, F.A. Fehintola montrait que la nevapirine prescrite simultanément avec l’artemether-lumefantrine (Coartem) réduisait de 70% la concentration du principe actif lumefantrine dans le sang infecté.
Ceci ne fait que confirmer des résultats obtenus en Afrique du Sud (T Kredo , Antimicrob Agents Chemother. 2011 Dec; 55(12):5616-23). L’artemether et la nevapirine sont métabolisés par le cytochrome P450 3A4 induit par la nevapirine.
Pauline Byakik à la Makerere University a elle aussi constaté que l’administration simultanée du Coartem avec efavirens diminuait les effets de l’artemether et de la lumefantrine. (J Antimicrob Chemother 2012, 67, 2213-2221). Le même effet a été décrit par T Kakuda et al., (HIV Therapy Workshop, Barcelona, 16-18 Mar 2012).
L’antagonisme a été observé non seulement avec les dérivés de l’artemisinine mais également avec les dérivés de la quinine chez la femme enceinte. (K Kayentao, Am J Trop Med Hyg. 2014 Mar; 90(3):530-4). L’amodiaquine est 40% moins concentrée dans le sang des patients traités par neviparine (K Scarsi et al., J Antimicrob Chemother 2014, 69, 1370-76).
Le traitement intermittent à la méfloquine se traduit par une transmission accrue du VIH de la mère à l’enfant. (R Gonzalez et al., PLOS Medecine 2014, 11-9).
Beaucoup de touristes européens utilisent la malarone comme prophylactique. La molécule active de ce remède, l’atovaquone-proguanil se retrouve à de plus faibles concentrations chez les patients prenant en même temps de l’efavirens, du lopinavir, du ritonavir ou du atazanavir (van Luin M1, AIDS. 2010 May 15;24(8):1223-6).
Ces observations ont été résumées par Van Geertruyden JP. (Clin Microbiol Infect. 2014 Apr;20(4):278-85). Les interactions pathophysiologiques et epidemiologiques entre VIH. et pathogènes tropicaux, surtout ceux du paludisme, commencent à créer de fortes appréhensions dans les pays du Sud. Deux décennies de recherches confirment que la liaison entre l’immunosuppression du VIH est corrélée avec l’incidence du paludisme, avec les échecs dans son traitement et les cas de malaria sévère. Le risque d’un développement de la résistance aux traitements prescrits par l’OMS se trouve donc multiplié. La recommandation de l’OMS de juin 2013 de traiter les mères qui viennent d’accoucher et les nouveau-nés pendant la période d’allaitement avec des ARV chaque jour pendant six semaines n’a pas trouvé de confirmation scientifique de ses bienfaits lors d’essais cliniques. Le prétendu effet contre le paludisme et sa transmission n’a pas pu être constaté (P Natureebaet al., JID 2014 :210). The Lancet a publié une étude qui montre plutôt un effet contraire : le ritonavir et le saquinavir réduisent de plus de 50% le nombre d’erythrocytes phagocytés par les macrophages (S Nathoo et al., The Lancet, 362, 2003. 1039-1041).
Le plus grave c’est que le traitement antiretroviral augmente la fréquence des porteurs asymptomatiques de Plasmodium. De 15.4 à 44.4 selon une étude du Niger. Et ces porteurs asymptomatiques ont une densité de parasites beaucoup plus élevée. (Adetifa et al., Niger Postgrad Med J, 2008 15. 141-145).
Une bombe à retardement pour l’Afrique.
Déjà en 2006 F Nosten et U d’Alessandro avaient insisté pour qu’on fasse des études approfondies sur les interactions entre antirétrovirax et antipaludiques, surtout chez les femmes enceintes (Curr Drug Saf 2006, Jan 1-15).
Ceci n’a pas empêché une inondation du marché africain avec ces deux remèdes. Un business qui se chiffre dans les milliards de dollars.
A team of medical doctors in RDCongo, Jerome Munyangi and Michel Idumbo, have run randomized clinical trials on a large scale in the Maniema province with the participation of some 1000 malaria infected patients. The trials were run in conformity with the WHO procedures and compared Artemisia annua and Artemisia afra with ACTs (Coartem and ASAQ). For all the parameters tested herbal treatment was significantly better than ACTs: faster clearance for fever and parasitemia, absence of parasites on day 28 for 99.5% of the Artemisia treatments and 79.5% only for the ACT treatments. A total absence of side effects was evident for the treatments with the plants, but for the 498 patients treated with ACTs, 210 suffered from diarrhea, and/or nausea, pruritus, hypoglycemia etc. The efficiency was equivalent for Artemisia annua and Artemisia afra. More important even is the observation for the total absence of gametocytes after 7 days treatment with the herb. A tremendous hope for malaria eradication. The results have been communicated to the local health authorities, and to the Ministries of Health and Research in the RDCongo who were supportive of these trials. The draft of a paper is almost ready and will be submitted to a peer reviewed scientific journal.
The financial support for the trials comes from the association MoreforLess in Paris.
This is not the only clinical trial run in 2015 with Artemisia annua aqueous infusions. In Benin the University of Abomey, together with the Universities of Louvain and of Liege, run a large scale trial with Artemisia annua grown in Benin. The trial involved 130 malaria infected patients. Fever clearance was evident after 48 hours and parasitemia decreased by 70% already on the first day, and remained 100 % absent on days 14 and 28. No side effects were noticed. The research team from Benin strongly recommends for African countries to replace the expensive and now often ineffective ACTs by Artemisia annua tea (H Zime-Diawara et al., Int J Biol Chem Sci 2015, 9-2, 692-702).
These results confirm results obtained by the association IFBV-Belherb and her partners in many small scale trials in several African countries over the last 6 years. Therapeutic efficiency always was > 95% and prophylaxy was noticed and documented. The abstracts or peer reviewed papers of all these trials are available on request.
In parallel with the clinical trials run by a team of medical doctors in the province of Maniema on the efficiency of Artemisia annua and Artemisia afra against malaria, (see Breaking News Jan.5 on http://www.malariaworld.org) they have completed another large scale randomized, double blind trial against schistosomiasis, Artemisia vs Praziquantel.
The results confirm previous anecdotic results from several countries in Africa. Both arms in this trial had 400 infected patients. The treatment efficiency was 97 % in the Artemisia arm and 71% in the Praziquantel arm. No side effects were noticed in the Artemisia treatment. 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.
Schistosomiasis kills 150 000 Africans per year and more than 70 000 000 are infected. A neglected disease in neglected, poor populations where the only existing drug, Praziquantel, loses efficiency year after year.
These young African doctors have run these trials despite the oposition and intimidations of BigpharmaWHO. They will win the battle against neglected tropical diseases where Western chemical monotherapies have failed
Jerome Munyangi, Michel Idumbo, Lucile Cornet-Vernet, Pierre Lutgen
n diabetes and malaria from PalestineAs stated in previous blogs diabetes is on the rise everywhere. It is a debilitating and often fatal disease per se but it also increases the incidence of malaria because higher glucose contents in the blood are a fertile terrain for Plasmodium falciparum.
It is the general belief that malaria patients are poor in antioxidant defenses and that supplementation with antioxidants (vitamins, polyphenols) will alleviate the severity of malaria infections. It is thus surprising that the University of Al Quds finds that the total antioxidant status in type 2 diabetic patients in Palestine in significantly higher compared to control subjects. The study involved 212 diabetic subjects and 208 normal subjects (AT Kharroubi et al., J Diabetes Research, 2015 ID461271).
A similar finding had already been made in Romania on a reduced number of 15 patients: the total antioxidant capacity of plasma increased in type 2 diabetes (O Saviu et al, J Internat Med Res. 2012, 40, 709-716).
Already in 1999 it had been found that in diabetic condition antioxidant enzyme levels are elevated (M Ramanathan et al., Indian J Exp Biol 1999, 37, 182-3). It is generally accepted that reactive oxygen species and oxidative stress impair beta-cell function in the pancreas and reduce insulin secretion. Pancreatic islets are known for their extremely low antioxidative defense status and their unusual susceptibility to ROS (E Gurgul et al., Diabetes 2004, 53, 2271-78). And any increase in ROS can markedly impair insulin secretion.
Confronted with low levels of insulin, which has anti-inflammatory properties (Aljada et al., Metab Clin Exp 55, 2006, 1177-85), diabetic beta-cells try self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses (Gregory Lacraz et al, PLoS ONE 2009, 4-8, e6500). But often this protection is not sufficient and it is often proposed to supplement antioxidants in the treatment of diabetes. A review published in 2011 reviews all human clinical trials where antioxidants were studied as an adjuvant to standard diabetes treatment. The authors came to the surprising conclusion that there is not any established benefit for antioxidants use in the management of diabetic complications. They interfer with the physiologic redox balance. Therefore, routine vitamin of mineral supplementation should not be generally recommended (S Golbidi et al, Curr Diabetes Rev 20117, 106-25).
One of the neglected side effects of diabetes is the generation of large quantities of hydrogen peroxide.
Healthy pancreatic beta-cells exhibit a dramatic response to nutrients and glucose through hypersecretion of insulin in order to maintain energy homeostasis. Many studies have suggested that chronic exposure of pancreatic beta-cells to high levels of glucose may contribute to impaired beta-cell function, leading to the production of ROS. Intriguingly, compared to other tissues, beta-cells have a lower abundance of antioxidant defense such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx). The ROS produced include superoxide and hydroxyl radicals. These may subsequently be converted to hydrogen peroxide (Y Ihara et al., Diabetes. 1999 , 48 927-32). A study from Tunesia shows that the hydrogen peroxide concentration in plasma is increased fourfold in type 2 diabetes compared to controls (A Msolly et al., J Cardiovascul Disease, 2013, 1, 48-51). It was based on 200 confirmed type 2 diabetes patients and 200 controls recruited in the regional blood transfusion center of Sousse. There was a strong positive linear correlation between glycated hemoglobin and hydrogen peroxide, between free fatty acids and hydrogen peroxide concentration and a negative correlation between quantitative insulin index and hydrogen peroxide. Another paper documents that insulin treatment reduces the hydrogen peroxide concentration in blood (A Bravard et al., Am J Physiol Endocrinol Metab, 2011, 300, E581-E591).
At sites of inflammation hydrogen peroxide appears to modulate the inflammatory process and inactivates NFκB. Due to its permeability in many tissues, it operates as an intracellular and intercellular messenger, but at high concentrations it becomes toxic, especially in insulin producing cells known for their extremely low antioxidant equipment against hydrogen peroxide (B Halliwell et al., FEBS Letters 2000, 486, 10-13). Hydrogen peroxide could also plays a role in the regulation of renal function. Renal medullary hydrogen peroxide production is increased in diabetics (D Patinha et al., Life Sci, 2014, 108, 71-9).
Hydrogen peroxide has another side effect. It decreases endothelial nitric oxide synthase NOS promoter activity (Kumar S et al., DNA Cell Biol. 2009, 2:119-29). It is well documented that NOS and NO generated by this enzyme have important endothelial functions and its inhibition may explain most of the cardiovascular problems generated by diabetes.
Several biomarkers of metabolic acidosis, including lower plasma bicarbonate have been associated with insulin in cross-sectional studies. A team from Canada conducted a study called the “Nurses Health Study”. Plasma bicarbonate was measured in 630 women who did not have type 2 diabetes mellitus at the time of the blood draw in 1989 but developed the disease during 10 years of follow-up. The outcome was that higher plasma bicarbonate levels were associated with lower odds of incident type 2 diabetes mellitus (EI Mandel et al., CMAJ, 2012, 184, E179)
The pancreas generates a lot of sodium bicarbonate. The rate of decomposition of hydrogen peroxide has been measured in aqueous sodium carbonate solutions (0.1-1.0 M). It is decomposed in a few minutes and 10 times faster than in a sodium hydroxide solution (HH Lee et al., 2000, Tappi Journal)(U von Gunten et al, Ozone Science and Engineering Journal, 2000, 22, 305-328).
The role of bicarbonate and hydrogen peroxide in diabetes deserve much more research. Because it has an impact on malaria too. As the University of Quds has shown bicarbonate strongly contributes to the inhibition of beta-hematin crystallization (Suhair Jaber et al., J Pharmacy Pharmacol 2015, 3, 63-72).
It is astonishing and frustrating that the impact of diabetes on Plasmodium proliferation is known since more than 100 years. In 1912 Bass and Johnson reported that the addition of glucose was necessary for successful in vitro cultivation of the human malaria parasites Plasmodium falciparum and vivax. However, blood from a diabetic person was successfully used in the culture medium without addition of glucose. They also reported that the amount of quinine sufficient to control malaria infections was ineffective in this case. As a result of these observations they came to the conclusion that the elevated blood sugar from a diabetic patient provided a medium which could better support the growth and reproduction of parasites than could the blood of a non-diabetic person.
17 december 2015.