Toxicity of artemether and artesunate

Effets secondaires des dérivés de l'artemisinine

Some recent research, mostly in relation with the resistance to ACT pills and/or artesunate injections, has highlighted serious secundary health effects at the doses prescribed by WHO. The scientific literature describes a wide array : haemolytic, hepatotoxic, cytotoxic, neurotoxic, cardiotoxic, genotoxic, ototoxic, embryotoxic, spleenotoxic, hemolytic, atherosclerosis, spermatoxicity, immunodepressive effects of chemical artemisinine derivatives and artemisinin combined therapies (ACTs) Fears of emerging artemisin resistance in western Cambodia have promoted a series of clinical trials investigating if resistance can be overcome by increasing doses of drug. After 3 to 5 doses neutrophil counts were reduced in all groups and several patients required artesunate to be discontinued because of neutropenia. This study demonstrates that the dosing limit may have been reached Bethell D, Se Y, Lon C, Socheat D, Saunders D, Teja-Isavadharm P, Khemawoot P, Darapiseth S, Lin J, Sriwichai S, Kuntawungin W, Surasri S, Lee SJ, Sarim S, Tyner S, Smith B, Fukuda MM. Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria. dosing limit may have been reached. Clin Infect Dis. 2010 Dec 15;51(12): e105-14. doi: 10.1086/657402 A high risk of neutropenia in HIV-infected children following treatment with artesunate was also noticed in Uganda Anne F. Gasasira, Moses R. Kamya, Jane Achan, Tsedal Mebrahtu, Joan N. Kalyango, Theodore Ruel, Edwin Charlebois, Sarah G. Staedke, Adeodata Kekitiinwa, Philip J. Rosenthal, Diane Havlir, and Grant Dorsey. High Risk of Neutropenia in HIV-Infected Children following Treatment with Artesunate plus Amodiaquine for Uncomplicated Malaria in Uganda. Clin Infect Dis. (2008) 46 (7): 985-991. doi: 10.1086/529192 Artesunate stimulates the immune system at low doses and inhibits it at high doses. Methods of inhibition or killing cancer cells using an endoperoxide. US 5578637 Li T, Chen H Evluation of the immunosuppressive activity of artesunate in vitro and in vivo. International Immunopharmacology 2013, 16, 169-178. The results from a study in India revealed that artesunate caused significant alteration in oxidative parameters in dose-dependent manner. Administration of artesunate brought about significant decrease in activities of superoxide dismutase, glutathione, glutathione peroxidase, and glutathione reductase, whereas lipid peroxidation and glutathione-S-transferase activity were found to be significantly increased. The results obtained show that oxidative insult is incurred upon the intracellular antioxidant system of testis tissue by artesunate treatment. A Desai KR, Rajput DK, Patel PB, Highland HN. Ameliorative Effects of Curcumin on Artesunate-Induced Subchronic Toxicity in Testis of Swiss Albino Male Mice. Dose Response. 2015 Jun 26;13(2):1559325815592393. doi: 10.1177/1559325815592393 Higher doses are used in fixed formulations because in climatic zones III and IV artemisinin and derivatives are unstable and it is important that the amount of active drug present does not fall below the designated effective therapeutic dose before the expiry date. Haynes RK, Chan HW, Lung CM, Ng NC, Wong HN, Shek LY, Williams ID, Cartwright A, Gomes MF. Artesunate and dihydroartemisinin (DHA): unusual decomposition products formed under mild conditions and comments on the fitness of DHA as an antimalarial drug. ChemMedChem. 2007 Oct;2(10):1448-63. One of the side effects of the higher doses is the dormancy effect induced in plasmodium. The parasite encapsulates itself against the aggressive peroxide artesunate and reawakens at the end of the treatment. It has recently been confirmed in vivo. Alexis N. LaCrue, Misty Scheel, Dennis E. Kyle. Effects of Artesunate on Parasite Recrudescence and Dormancy in the Rodent Malaria Model Plasmodium vinckei. PLOS. 2011. doi.org/10.1371/journal.pone.0026689 This may be one of the causes of resistance. This dormancy effect is similar, but not related to the sequestration and cytoadherence of falciparum parasitized erythrocytes. Sequestration of these erythrocytes in capillaries or placenta may protect the parasite from destruction. David D. Roberts, James A. Sherwood, Steven L. Spitalnik, Lindsey J. Panton, Russell J. Howard, Vishva M. Dixit, William A. Frazier, Louis H. Miller & Victor Ginsburg. Thrombospondin binds falciparum malaria parasitized erythrocytes and may mediate cytoadherence. Nature 318, 64 - 66 (07 November 1985); doi:10.1038/318064a0 This massive administration of high doses of artemisinin derivatives is in contradiction with the dose of 34 mg for a human recommended for the new ozonide antimalarial OZ439. Moehrle JJ, Duparc S, Siethoff C, van Giersbergen PL, Craft JC, Arbe-Barnes S, Charman SA, Gutierrez M, Wittlin S, Vennerstrom JL. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br J Clin Pharmacol. 2013 Feb;75(2):524-37. doi: 10.1111/j.1365-2125.2012.04368.x. The artemisinin dose recommended by WHO/MAL/98-1086 on the first days of treatment is 1 400 mg. But the doom of OZ439 is probably going to be the same as for all mono-therapies: resistance. And it appears in a PubMed search that no further research is active on these molecules In Nigeria in a study on rats it was found that hepatoxicity and hemolysis were clearly associated with artesunate. The hepatoxicity effect was monitored in the rats as a function of aspartase transaminase (ASAT), alanine transaminase (ASAT) which both increased drastically. The hemolytic effect was monitored by the packed cell volume, bilirubin, hematocrit and serum albumin. Artemisinin significantly increases ALAT in rats. Omotuyi, I. O, Nwangwu S. C., Okugbo, O. T., Okoye, O. T., Ojieh, G. C.3 and Wogu, D. M. Hepatotoxic and hemolytic effects of acute exposure of rats to artesunate overdose. African Journal of Biochemistry Research Vol.2 (5), pp. 107-110, May, 2008 Udobre A., Edoho J.E., Eseyi O. and Etim I.E (2009). Effects of Artemisinin with Folic acid on the activities of Aspartate Amino Transferase, Alanine Amino Transferase and Alkaline Phosphatase in Rats. Asian J. Biochem., 4(2): 55-59 Acute hepototoxicty following administration of artesunate in guinea pigs was also noticed in other trials in Nigeria. H Nwanjo, G Oze. Acute Hepatotocixity Following Administration Of Artesunate In Guinea Pigs. The Internet Journal of Toxicology. 2006 Volume 4 Number 1. In humans hepatotoxicity can be particularly severe if artesunate is used in combination with HIV antiretroviral drugs German P, Greenhouse B, Coates C et al. Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz. Clin Infect Dis 2007; 44: 889–891. The document WHOPAR 06/2011 MA058 recognizes that artesunate/amodiaquine 100/270 mg tablets may result in severe hepatotoxicity. The histological effect of oral administration of artesunate on the liver in wistar rats confirmed a toxic effect on liver cells and mild inflammation of the portal tracts. The generation of ROS leads to the accumulation of lipid peroxides leading to change in permeability of the cells. The authors conclude that self-medication with artesunate should be discouraged. A.M. Izunya, A.O. Nwaopara, A. Aigbiremolen, M.A.C. Odike, G.A. Oaikhena and J.K. Bankole. Histological Effects of Oral Administration of Artesunate on the Liver in Wistar Rats. Res J Appl Sci eng and Technology, 2-4, 2010, 314-318 Another recent study from Nigeria Abolaji AO, Eteng MU, Omonua O, Adenrele Y. Influence of coadministration of artemether and lumefantrine on selected plasma biochemical and erythrocyte oxidative stress indices in female Wistar rats. Hum Exp Toxicol. 2013 Feb;32(2):206-15. doi: 10.1177/0960327112464666. shows that the co-administration of artemether and lumefantrine causes significant increase in glutathione peroxidase and malondialdehyde levels and may thus increase the risk of atherosclerosis. Artemether can aggravate anemia when administered to malaria patients. In the absence of malarial parasite infection, the drugs induce oxidative stress in the ovary and uterus and disrupt hormonal balance in the rats AO Abolaji, OA Adesanoye, I Awogbindin. Endocrine disruption and oxidative stress implications of artemether–lumefantrine combination therapy in the ovary and uterus of rats. Human & Experimental Toxicology Jan 25 2016 Osonuga IO, Osonuga OA, Osonuga A, Onadeko AA, Osonuga AA. Effect of artemether on hematological parameters of healthy and uninfected adult Wistar rats. Asian Pac J Trop Biomed. 2012 Jun; 2(6):493-5. doi: 10.1016/S2221-1691(12)60083-5. The liver is considerably more affected than the kidney by administration of artemether or Coartem Adaramoye OA, Osaimoje DO, Akinsanya AM, Nneji CM, Fafunso MA, Ademowo OG. Changes in antioxidant status and biochemical indices after acute administration of artemether, artemether-lumefantrine and halofantrine in rats. Basic Clin Pharmacol Toxicol. 2008 Apr;102(4):412-8. doi: 10.1111/j.1742-7843.2008.00211.x. A Brazilian study showed that liver cells treated with artemisinin and artesunate showed a significant dose-dependent increase in the cells with DNA damage at all concentrations tested Aquino I, Tsuboy MS, Marcarini JC, Mantovani MS, Perazzo FF, Maistro EL. Genotoxic evaluation of the antimalarial drugs artemisinin and artesunate in human HepG2 cells and effects on CASP3 and SOD1 gene expressions. Genet Mol Res. 2013 Jul 24;12(3):2517-27. doi: 10.4238/2013.July.24.6. O. T. Soniran, O. A. Idowu, . L. Ajayi, and I. C. Olubi. Comparative Study on the Effects of Chloroquine and Artesunate on Histopathological Damages Caused by Plasmodium berghei in Four Vital Organs of Infected Albino Mice. Malar Res Treat. 2012; 2012: 960758. doi: 10.1155/2012/960758 Proliferation of megakaryoblasts was induced by artesunate in the spleen of Albino mice, but not by chloroquine. The authors claim that self-medication with artesunate should be prohibited. Spleen enlargement due to artemether is known since decades. High doses of artemether cause progressive degeneration of the renal tissue in rats RO Akomolafe, IO Adeoshun, JB Fakunle, EO Iwalewa, AO Ayoka, OE Ajayi, OM Odeleye, BO Akanji. Effects of artemether on the plasma and urine concentrations of some electrolytes in rats African Journal of Biotechnology. Afric J Biotechnology, 10:20, 4226-33, 2011. A study from Nigeria shows that artesunate dramatically increases ALAT and ASAT values, indicative of serious liver toxicity Aniefiok Udobre, Edoho J. Edoho, Olorunfemi Eseyin and Emmanuel I. Etim. Effect of Artemisinin with Folic Acid on the Activities of Aspartate Amino Transferase, Alanine Amino Transferase and Alkaline Phosphatase in Rat. Asian Journal of Biochemistry, 4, 2009, 55-59 DOI: 10.3923/ajb.2009.55-59 Other Nigerian studies show that artemether-lumefantrine increases urea by 53.2 % and may cause toxicity to renal and reproductive functions. Another study found severe sodium-artesunate diuresis in a patient with malaria Syed Ahmed Zaki, Preeti Shanbag, Vijay Lad, Prithi Shenoy. Sodium artesunate-induced diuresis in a patient with malaria. Indian journal of pharmacology 43:4 2011 Jul pg 472-3 Artesunate is spermatotoxic. PI Jewo, JA Shittu, MC Izegbu, OA Adesanya, LC Saalu, OA Ashiru. Modulatory Effects of Ascorbic Acid on Spermatoxicity of Artesunate in Rats. Nigerian Medical Practitioner Vol. 53 (4) 2008: pp. 62-65 An electrocardiographic study performed on Ghanaian children in 2012, 5 years after the introduction of ASAQ, showed that artesunate-amodiaquine caused a high incidence of brachycardia. George O Adjei, Collins Oduro-Boatey, Onike P Rodrigues, Lotte C Hoegberg, Michael Alifrangis, Jorgen A Kurtzhals and Bamenla Q Goka. Electrocardiographic study in Ghanaian children with uncomplicated malaria, treated with artesunate-amodiaquine or artemether-lumefantrine. Malaria Journal 201211:420. DOI: 10.1186/1475-2875-11-420 Natural cocoa powder proved to possess cardioprotective and renoprotective potential during artemether-lumefantrine administration IJ Asiedu-Gyekye, MA Seidu, BB N’guessan A dietary strategy for the management of artemether-lumefantrine-induced cardiovascular and renal toxicity. BMC Complementary and Alternative Medicine 2016, 16-384. Another study in Nigeria on rats Chiagoziem A. Otuechere, Gloria Edewor, Oluwafemi Ezekiel Kale, and Martins Ekor. Subacute Therapeutic Dosing of Artemether-Lumefantrine and Artesunate-Amodiaquine Combination Preserves Plasma Cholesterol, Renal Antioxidant Status, and Organ Weights in Rats. Malaria Research and Treatment.Volume 2012 (2012), Article ID 257986, doi.org/10.1155/2012/257986 showed that ASAQ afforded a 27.2% heart weight decrease when compared with control. The authors also state that caution is required and that chronic doses may predispose to renal oxidative stress. Arteether has never been introduced mainly because of cardiologic concerns. Andrea Bosman, Review for inclusion of a drug in the WHO essential drugs list. Arteether, artemotil, CDS/RBM, 18 March 2002 Derivatives of artemisinin exhibit potent immunosuppressive activity. J-X Wang, W Tang, L-P Shi, J Wan, R Zhou, J Ni, Y-F Fu, Y-F Yang, Y Li,2 and J-P Zuo. Investigation of the immunosuppressive activity of artemether on T-cell activation and proliferation Br J Pharmacol. 2007 Mar; 150(5): 652–661. Artesunate concentrations between 0.1-1.5 microg/ml reduced lymphocyte production in a generally dose dependant manner. Veerasubramanian P, Gosi P , Limsomwong C , Walsh DS . Artesunate and a major metabolite, dihydroartemisinin, diminish mitogen-induced lymphocyte proliferation and activation. The Southeast Asian Journal of Tropical Medicine and Public Health [2006, 37(5):838-847] The authors claim that further work is warranted to define the mechanisms involved and wether this affects malaria treatment. Another research work confirmed the genotoxic and cytotoxic effect of artesunate in cultured human lymphocytes Gomes LM, Vieira PC , Corrêa RM , Santana PD , Miranda MS , Burbano RM , Bahia MO . In vitro evaluation of the genotoxic and cytotoxic effects of artesunate, an antimalarial drug, in human lymphocytes. Environmental and Molecular Mutagenesis [2011, 52(7):590-594] DOI: 10.1002/em.20659 But the mechanism of this inhibitory effect on lymphoproliferation is unknown. TNF-α levels were also reduced in patients treated with artesunate Ittarat W, Udomsangpetch R, Chotivanich KT, Looareesuwan S.W Ittarat et al., Southeast Asian J Trop Med, 30, 1999, 7-10). The effects of quinine and artesunate treatment on plasma tumor necrosis factor levels in malaria-infected patients. Southeast Asian J Trop Med Public Health. 1999 Mar; 30(1):7-10. which obviously has an effect on the inflammatory process. In normal mice artemisinin and arteether exhibit a pronounced inhibition of the humoral reponse Tawfik AF , Bishop SJ , Ayalp A , el-Feraly FS . Effects of artemisinin, dihydroartemisinin and arteether on immune responses of normal mice. International Journal of Immunopharmacology 1990, 12(4):385-389. DOI: 10.1016/0192-0561(90)90019-J The majority of these studies on immunity also find a reduction of CD4+ and CD8+ T cells which could be detrimental in HIV infections. Several recent papers Shah SN, Smith EE, Obonyo CO, Kain KC, Bloland PB, Slutsker L, Hamel MJ. HIV immunosuppression and antimalarial efficacy: sulfadoxine-pyrimethamine for the treatment of uncomplicated malaria in HIV-infected adults in Siaya, Kenya. J Infect Dis. 2006 Dec 1;194(11):1519-28 Van Geertruyden JP, Mulenga M, Mwananyanda L, Chalwe V, Moerman F, Chilengi R, Kasongo W, Van Overmeir C, Dujardin JC, Colebunders R, Kestens L, D'Alessandro U. HIV-1 immune suppression and antimalarial treatment outcome in Zambian adults with uncomplicated malaria. J Infect Dis. 2006 Oct 1;194(7):917-25. have shown that in patients with low CD4 count it was impossible to lower the high plasmodium load to zero, even with the strongest antimalarial drug known: dihydroartemisinin Y.M. Tatfenga, J.C. Ihongbeb, M. Okoduab, F. Oviasogiec, J. Isiborb, S. Tchougangc, E. Tambod & T. Otegbeyeb. CD4 count, viral load and parasite density of HIV positive individuals undergoing malaria treatment with dihydroartemisinin in Benin City, J Vect Borne Dis 44, June 2007, pp. 111–115 After a malaria attack the CD4 count remains low for several months in persons which had a low CD4 baseline at the moment of the infection. The haemolytic effect is well described in the following paper Angela Corpolongo, Pasquale De Nardo, Piero Ghirga, Elisa Gentilotti, Rita Bellagamba, Chiara Tommasi, Maria Grazia Paglia, Emanuele Nicastri and Pasquale Narciso. Haemolytic anaemia in an HIV-infected patient with severe falciparum malaria after treatment with oral artemether-lumefantrine. Malaria Journal 201211:91 DOI: 10.1186/1475-2875-11-91 The patient described in their article presented with fever, headache after returning from Central African Republic. He had been treated with oral artemether and lumefantrine. The blood analysis revealed acute renal failure. Hereditary or auto-immune disorders were excluded. There are a few other cases described in the same paper of haemolytic anaemia during or after treatment with i.v. artesunate alone or combined with mefloquine: the case of a Nigerian male with severe P. falciparum malaria initially treated with mefloquine. After one day of treatment, because of the worsening clinical condition of the patient and the increase of the parasitaemia, therapy with i.v. artesunate was initiated. Parasite clearance was obtained within 20 hours after the first administration of artesunate, but fever persisted for a further seven days and haemolytic anaemia was observed, requiring blood transfusion; the case of a young woman with P. falciparum malaria who was successfully treated with i.v. artesunate, but showed worsening anaemia after artesunate administration ; severe haemolytic anaemia and jaundice on day 11 after i.v. artesunate administration in a 68-year-old Japanese woman affected by severe malaria; a series of 25 travellers with severe malaria treated with i.v. artesunate. Among them, six patients developed haemolytic anaemia week after treatment possibily related to artesunate or had persistent signs of haemolytic activity until six weeks after the first dose of i.v. artesunate. In this case series, patients with post-treatment haemolysis had received a higher cumulative dose of i.v. artesunate and were treated for longer periods. A recent study in Nigeria PC Chikezie, Studies of Methemoglobin Concentrations of Three Human Erythrocyte Genotypes (Hb AA, Hb AS, and Hb SS) in the Presence of Five Antimalarial Drugs Iranian J of Blood and Cancer, 2009, 4, 151-157 compares the effect of five antimalarial drugs on methemoglobin concentrations in erythrocytes. The five drugs showed a concentration dependent elevation of plasma methemoglobin. Coartem® showed the highest propensity. Another study by the same authors P. C. Chikezie, A. A. Uwakwe and C.C. Monago. Comparative osmotic fragility of three erythrocyte genotypes (HbAA, HbAS and HbSS) of male participants administered with five antimalarial drugs. Afr J Biochem Res. 4:3 57-64, 2010 ascertained the osmotic fragility of erythrocytes after administration of the 5 same antimalarial drugs (Fansidar-SP, Halofantrine, Quinine, Coartem). All caused a rapid accumulation of ROS overwhelming the antioxidant defense capacities of the erythrocytes and caused depletion of erythrocyte glutathione concentration. Again the most aggressive effect on the average was noticed for Coartem®. Dihydroartemisinin is known to cause embryonic erythrocyte depletion and a significant delay in erythroid differentiation. Sara Finaurinia, Luisa Ronzonib, Alessandra Colanceccob, , Alessandra Cattaneod, Maria Domenica Cappellinib, Stephen A. Warde, Donatella Taramellia, Selective toxicity of dihydroartemisinin on human CD34+ erythroid cell differentiation. Toxicology. Volume 276, Issue 2, 9 October 2010, Pages 128–134 The derivatives of artemisinin are strong peroxides. They create radicals and reactive oxygen species which kill the parasites but which at high doses might damage cortical and brain stem neurons. Gabriele Schmuck, Elke Roehrdanz, Richard K. Haynes and Regine Kahl. Neurotoxic Mode of Action of Artemisinin. Antimicrob Agents and Chemother. 46, 2002, 821-827 and are cytotoxic to many other cells. The genotoxicity of artesunate was studied in Brazil on mice. Aquino I, Perazzo FF, Maistro EL. Genotoxicity assessment of the antimalarial compound artesunate in somatic cells of mice. Food Chem Toxicol. 2011 Jun;49(6):1335-9. doi: 10.1016/j.fct.2011.03.016. Artesunate was administered by oral gavage at doses of 5, 50 and 100 mg/kg. Artesunate showed weak genotoxic effects at low doses and severe (clastogenic effects) at high doses. The authors claim that the data obtained suggest caution about either continuous or high-dose use of artesunate by humans. Similar results were obtained by another research team in Brazil. Their results showed that artesunate is a genotoxic and cytotoxic compound in cultured human lymphocytes. A significant increase in the frequency of apoptotic and necrotic cells was observed. Mota TC, Cardoso PC, Gomes LM, Vieira PC, Corrêa RM, Santana PD, Miranda MS, Burbano RM, Bahia MO. In vitro evaluation of the genotoxic and cytotoxic effects of artesunate, an antimalarial drug, in human lymphocytes. Environ Mol Mutagen. 2011 Aug;52(7):590-4. doi: 10.1002/em.20659. Epub 2011 Jul 4. A study from Iran shows that pure artemisinin leads to cell injury in MDCK kidney cells in concentration dependent manner. Amir Ali Shahbazfar, Payman Zare, Hemn Mohammadpour and Hossein Tayefi-Nasrabadi. Effects of different concentrations of artemisinin and artemisinin-iron combination treatment on Madin Darby Canine Kidney (MDCK) cells. Interdiscip Toxicol. 2012 Mar; 5(1): 30–37. doi: 10.2478/v10102-012-0006-5 There is also increasing evidence that the oxidative stress induced by artemisinin derivatives plays a major role in the pathogenesis of diabetes C F M Lima, Tese de Doutoramento, Universidade do Minho, Nov 2006 This in turn has an important role in causing the secondary complications of diabetes, such as atherosclorosis, nephropathy, retinopathy and neuropathy. Artemisinin reduces intracellular ATP levels and the potential of the inner mitochondrial membrane below the cytotoxic concentration range, with these effects being most dominant in the brain stem cultures. Surprisingly, there were substantial effects on cortical neurons after 7 days and on astrocytes after 1 day. Toxic brainstem encephalopathy was noticed after artemisinin treatment for breast cancer. Panossian LA, Garga NI, Pelletier D. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol. 2005 Nov;58(5):812-3. Artesunate and artemether rapidly degrade into dihydroartemisinin which is claimed by pharmaceutical companies to be 10 times more effective against malaria than artemisinin. Artemisinin itself does not metabolize into dihydroartemisinin and stays much longer in the plasma. This might be one of the reasons why Artemisia annua tea infusions, despite the fact that they contain much less active molecules than ACTs, might be as effective. A very recent paper from Nigeria confirms all the concerns listed before. E. T. Olayinka and A.Ore. Alterations in Antioxidant Status and Biochemical Indices Following Administration of Dihydroartemisinin-Piperaquine Phosphate (P-ALAXIN®). IOSR Journal of Pharmacy and Biological Sciences (IOSR-JPBS)e-ISSN: 2278-3008. Volume 5, Issue 4 (Mar. – Apr. 2013), pp 43-53 ” Our results suggest that the therapeutic doses of P-ALAXIN (DHA-piperaquine) induced marked renal and hepatic failure and decreased the levels of antioxidant defense systems, with the effect more pronounced in double therapeutic doses. As such caution should be taken in administering the drug…” All these findings are especially worrisome for the use of higher doses of artesunate required for pregnant women because immunity is temporarely disrupted in pregnancy. Non-immune or immunodepressed patients require higher doses for an adequate therapeutic response. Artesunate also causes embryo death in animals by causing severe anemia with higher drug concentrations. Clark RL, White TE, A Clode S, et al, “Developmental Toxicity of Artesunate. Birth Defects Res B Dev Reprod Toxicol , 2011, 92(1) 2011, 92(1):52-68. Artesunate increased embryolethality and the incidence of limb long bone malformations on the absence of overt maternal toxicity. Boareto AC1, Müller JC, de Araujo SL, Lourenço AC, Lourenço EL, Gomes C, Minatovicz B, Lombardi N, Paumgartten FR, Dalsenter PR. Study on the developmental toxicity of combined artesunate and mefloquine antimalarial drugs on rats. Reprod Toxicol. 2012 Dec;34(4):658-64. doi: 10.1016/j.reprotox.2012.10.004. Epub 2012 Oct 13. In cancer treatment doses of artemisinin 10-20 times higher than for malaria are required. It was found D'Alessandro S, Basilico N, Corbett Y, Scaccabarozzi D, Omodeo-Salè F. Saresella M, Marventano I, Vaillant M, Olliaro P, Taramelli D. Hypoxia modulates the effect of dihydroartemisinin on endothelial cells. Biochem Pharmacol. 2011 Sep 1;82(5):476-84. IF 4.889 that these lead to inhibition and apoptosis of endothelial cells and lipid peroxidation. A recent study from Mali Issaka Sagara, Bakary Fofana, Jean Gaudart, Bakary Sidibe, Amadou Togo, Sekou Toure, Kassim Sanogo, Demba Dembele, Alassane Dicko, Roch Giorgi, Ogobara K. Doumbo, and Abdoulaye A. Djimde. Repeated Artemisinin-Based Combination Therapies in a Malaria Hyperendemic Area of Mali: Efficacy, Safety, and Public Health Impact. Am J Trop Med Hyg. 2012 Jul 1; 87(1): 50–56. doi: 10.4269/ajtmh.2012.11-0649 shows, that all ACT treatments, but mainly Coartem lead to creatinemia (high creatinine). Inflammatory effects have been several times reported for ACTs. In Ethiopia Ashenafi Assefa, Moges Kassa, Gemechu Tadese, Hussen Mohamed, Abebe Animut and Tesfayae Mengesha, Therapeutic efficacy of Artemether/Lumefantrine (Coartem®) against Plasmodium falciparum in Kersa, South West Ethiopia. Parasites & Vectors20103:1. DOI: 10.1186/1756-3305-3-1 a study revealed the development of oral inflammation (oral ulcer) in 7.2% of the patients treated with Coartem. Clinicians in the area had reported the same side effect in the past. In Mozambique audiometric changes were noticed after the treatment with co-artemether. A significantly greater hearing loss than for controls was noticed on 150 subjects receiving artemether-lumefantrine treatment of uncomplicated falciparum malaria. A case control auditory evaluation of patients treated artemether-lumefantrine. Toovey et al., Trans R Soc Trop Med Hyg, 2004, 98:5, 261-7 On the basis of these otometric results the authors recommend that the neurotoxicity of artemisinins be more fully evaluated. Worrisome is also the finding of research in Nigeria which indicates that high doses of artesunate may cause inflammation of the testicles and aggravate male infertility. AM Izunya, AO Nwaopara, AE Aigbiremolen, MAC Odike, GA Oaikhena, JK Bankole. Histological studies of the toxicity of artesunate on the testes in Wistar rats Research Article Biology and Medicine, 2 (2): 49-56, 2010 A previous study in Nigeria had shown that artesunate decreases the testosterone level by 37%., even at subclinical and clinical doses, an alarming situation. Obianime AW, Aprioku JS. Comparative study of artesunate, ACTs and their combinants on the spermatic parameters of the male guinea pig. Niger J Physiol Sci . 2009. 24:1–6 Many antimalarial drugs have been associated with male reproductive dysfunction. Chloroquine has been reported to reduce sperm motility and hence fertility by a reduction in the average number of fetuses of cohabited female rats. Artesunate has also been shown to cause a decrease in sperm motility in guinea pigs. This effect on reproductive parameters has been described in guinea pigs AW Obianime and JS Aprioku. Mechanism of action of artemisinins on biochemical, hematological and reproductive parameters in male guinea pigs. Internat J Pharmacol 2011, 7(1) 84-95 The effect on sperm count and androgenic deficiency has also been described Singh S, Giri A, The antimalarial agent artesunate causes sperm DNA damage and hepatic antioxidant defense in mice. 2016 DOI: 10.1016/j.mrgentox.2014.11.001 These studies suggest that artesunate has the potential to breach the testis-blood barrier and cause toxicity to male germ cells which may have implications in male reproductive toxicity. Nwanjo HU, Iroagba IN, Nnatuanya IN, Eze NA. Antifertility activity of dihydroarteminisinin in male albino rats. The Internet Journal of Endocronoloy, 4:1, 2007 It was also found that long-term administration of artesunate could induce reversible infertility in rats which may act via distortion of blood-testis barrier formed by Sertoli cells. Stephen Akinsomisoye Olumide, Yinusa Raji. Long-term administration of artesunate induces reproductive toxicity in male rats. J Reprod Infertil 2011 Oct;12(4):249-60 Caution is also required during co-administration of artemether/lumefantrine with lopinavir/rotinavir (anti HIV drugs) where severe interactions have been noticed. Byakika-Kibwika P, Lamorde M, Mayito J, Nabukeera L, Namakula R, Mayanja-Kizza H, Katabira E, Ntale M, Pakker N, Ryan M, Hanpithakpong W, Tarning J, Lindegardh N, de Vries PJ, Khoo S, Back D, Merry C. Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J Antimicrob Chemother. 2012;67:2213–2221 The clinical significance of this needs to be evaluated. Artemisinin induces CYP3A4 and this might influence the efficiency of other drugs like lumefantrine or other molecules which are metabolized by this cytochrome. Artemisin induces resistance against the anti-cancer drug doxorubicin Riganti C, Doublier S, Viarisio D, Miraglia E, Pescarmona G, Ghigo D, Bosia A Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1alpha and P-glycoprotein overexpression. Br J Pharmacol. 2009 Apr;156(7):1054-66. doi: 10.1111/j.1476-5381.2009.00117.x. Coadministration of artemether and lumefantrine may increase the risks of atherosclerosis as well as liver and renal function impairments in the users. The drugs also promote oxidative stress in the erythrocytes Influence of coadministration of artemether and lumefantrine on selected plasma biochemical and erythrocyte oxidative stress indices in female Wistar rats. Abolaji AO, Eteng MU , Omonua O , Adenrele Y .Drug Metabolism and Molecular Toxicology Research Laboratories, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria. Human & Experimental Toxicology [2013, 32(2):206-215, DOI: 10.1177/0960327112464666 A recent study from UK on the risk of developing eye disorders after the use of antimalarial drugs by travellers provides evidence that there was an increased risk compared to non-users. Schneider , Adamcova M, Jick , Schlagenhauf , Miller , Rhein , Meier. Use of anti-malarial drugs and the risk of developing eye disorders. Travel Med Infect Dis. 2014 Jan-Feb;12(1):40-7. doi: 10.1016/j.tmaid.2013.07.007. A more recent toxicity study from the Beijing Institute of Pharmacology and Toxicology summarizes the problem. Yin J-y, Wang H-m, Wang Q-j, Dong Y-s, Han G, et al. 2014. Subchronic Toxicological Study of two Artemisinin Derivatives in Dogs. PLoS ONE 9.4: e94034 Following treatment with artesunate the authors observed a decreased heart rate, which was most likely due to cardiac conduction system damage, as well as a deceased RBC count, extramedullary hematopoiesis in the spleen and inhibition of erythropoiesis in the bone marrow. These findings show that the prolonged administration of low doses of these derivatives result in diverse toxicity profiles. Way back, there was so much convincing evidence of fetotoxicity of artemisinins in animal studies (mainly with intramuscular injection) that the deployment of these agents in humans outside China was delayed. A German review paper also offers a summary on the critical isssue of toxicity Efferth T, Kaina B. Toxicity of the antimalarial artemisinin and its dervatives. Crit Rev Toxicol. 2010 May;40(5):405-21. doi: 10.3109/10408441003610571 The authors emphasize the current knowledge on neurotoxicity, embryotoxicity, genotoxicity, hemato- and immunotoxicity, cardiotoxicity, nephrotoxicity, and allergic reactions. There is a paucity of large-scale clinical trials suitable to detect rare but significant toxicity. Therefore, a final and definitive statement on the safety of artemisinins still cannot be made. In contrast, animal experiments show considerable toxicity upon application of artemisinins. The lesson learned from animal and human studies is that long-term availability rather than short-term peak concentrations of artemisinins cause toxicity. Rapid elimination of artemisinins after oral intake represents a relatively safe route of administration compared to delayed drug release after intramuscular (i.m.) injection. This explains why considerable toxicities were found in the majority of animal experiments, but not in human studies. These studies should have been done 30 years ago ! Frightening ! Not necessarily for the majority of Africans who don’t have the money to buy several ACT treatments per year. But if an European working in Africa decides to take regular doses of ACT (Coartem or Coarsucam) to prevent or cure suspected malaria attacks he may end up with serious damage in his brain, in his liver, his blood. This paper uses relatively low doses of 6mg/kg/day for 3 months, inferior to the doses prescribed by WHO. The WHO/MAL/98.1086 document has never been cancelled « The recommended dose of ART is 20 mg/kg as loading dose and 10 mg/kg for the following days. But none of these hepatotoxic, haemolytic, cytotoxic, immunodepressive, cardiotoxic , atheriosclerosic effects has ever been observed by drinking Artemisia annua tea. Several studies Muzemil A. (2008) PhD thesis, Addis Ababa University. Mukinda JT, Syce JA. Acute and chronic toxicity of the aqueous extract of Artemisia afra in rodents. J Ethnopharmacol. 2007 May 30;112(1):138-44. Epub 2007 Feb 14. G Chu J Toxicol Sci. 2003 Dec;28(5):471-8. A Moufid and M Eddouks. Artemisia herba alba , a popular plant with potential medicinal properties, Pak J Biolog Sci. 2012, 15(24) 1152-1159 Muto T, Watanabe T, Okamura M, Moto M, Kashida Y, Mitsumori K G. Chuipet, Thesis, Université des Montagnes, 2012, Muto T, Watanabe T, Okamura M, Moto M, Kashida Y, Mitsumori K. Thirteen-week repeated dose toxicity study of wormwood (Artemisia absinthium) extract in rats. J Toxicol Sci. 2003 Dec;28(5):471-8. Idris Ahmed Issa and Mohammed Hussen Bule. Hypoglycemic Effect of Aqueous and Methanolic Extract of Artemisia afra on Alloxan Induced Diabetic Swiss Albino Mice . Evidence-Based Complementary and Alternative Medicine Volume 2015 (2015), Article ID 752486 doi.org/10.1155/2015/752486, Maria Kokkini. Evaluation of toxicity in infusions of Artemisia absinthium of Greek flora and determination of α- and β-thujone in them. 2nd International Conference on Food Safety and Regulatory Measures, http://www.omicsonline.org/ArchiveJFPT/food-safety-2016-proceedings.php have confirmed that Artemisia infusions is innocuous up to 5000 mg/kg of dried plant extracts and although it administers doses of artemisinin 100 x lower than those of the ACT pills, it cures >95% of the malaria infections. Of course there aren’t many clinical trial data studying chronic toxicity for regular consumption of Artemisia annua as WHO strictly forbids clinical trials with the plant. Many studies have shown that Artemisia annua stimulates the immune system. This effect is probably due to other constituents than artemisinin: essential oils, flavonoids, coumarins, polysaccharides, saponins, tannins, pentacyclic triterpenes. The research work from the University des Montagnes in Cameroon even indicates that Artemisia annua tea lowers the alanine aminotransferase (ALAT) and could be hepatoprotective. The outcome suggests that artesunate toxicity may possibly cause damages to the hepatocytes and liver function ; effect contrary to that of A. annua, who keeps cells alive and is heptoprotective. N k u i t c h o u - C h o u g o u o K. Ro s i n e D . , Kouamouo Jonas, Titilayo O. Johnson, Djeungoue P. Marie-Ange, Chuisseu Pascal, Jaryum, Kouemeni Lysette, Lutgen Pierre , Tane Pierre, Moudipa F. Paul. Comparative study of Hepatoprotective and Antioxidant Activities of Artesunate and A r t e m i s i a a n n u a Flavonoids on rats hepatocytes. Pharmacognosy conference Sao Paolo, Aug 29-30, 2016. Remains eventually the question if the consumption of Artemisia annua during long months or years might generate secondary effects. A six-month single-centre open-label extension study was conducted at the University of Otago, New Zealand, in patients with osteoarthritis of the hip or knee. Thirty-four patients entered the optional extension and 28 completed six months' treatment. Artemisia annua was well tolerated when taken for up to nine months. Hunt S, Stebbings S, McNamara D. An open-label six-month extension study to investigate the safety and efficacy of an extract of Artemisiaannua for managing pain, stiffness and functional limitation associated with osteoarthritis of the hip and knee. N Z Med J. 2016 Oct 28;129(1444):97-102

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