hepatoxicity, neurotoxicity, haemolysis, mutagenicity of high doses of artesunate - ACT

Hepatotoxic, cytotoxic, neurotoxic, genotoxic, embryotoxic, hemolytic, immunodepressive effects of chemical artemisinine derivatives (ACTs) at high doses.

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.
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 (D Bethell et al., Clin Infect Dis, Nov 2010). A high risk of neutropenia in HIV-infected children following treatment with artesunate was also noticed in Uganda (AF Gasasira et al., Clin Infect Dis 1. 2008, 992-993)

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. This may be one of the causes of resistance .

In Nigeria (O Omotuyi et al, Afr J Biochem Res, 2, 2008, 107-110) 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 dratically. The hemolytic effect was monitored by the packed cell volume, bilirubin, hematocrit and serum albumin. Acute hepototoxicty following administration of artesunate in guinea pigs was also noticed in other trials in Nigeria ( HU Nwanjo et al., The International J of Toxicol., 4, 2007, 1-5). In humans hepatotoxicity can be particularly severe if artesunate is used in combination with HIV antiretroviral drugs ( P.German et al., Clin Inf Diseases44, 2007, 889-891) The document WHOPAR 06/2011 MA058 recognizes that artesunate/amodiaquine 100/270 mg tablets may result in severe hepatotoxicity.

Derivatives of artemisinin exhibit potent immunosuppressive activity (JX Wang et al., Br J Pharmacol150, 2007, 652-661). Artesunate concentrations between 0.1-1.5 microg/ml reduced lymphocyte production in a generally dose dependant manner ( P Veerusubramanian et al., Southeast Asian J Trop Med , 37, 2006, 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 ( TC Mota et al., Env Mol Mutagen 52, 2011, 590-594.) But the mechanism of inhibitory effect on lymphoproliferation is unknown. In the same work a reduction of CD4+ and CD8+ T cells was noticed which could be detrimental in HIV infections. TNF-α levels were also reduced in patient treated with artesunate (W Ittarat et al., Southeast Asian J Trop Med, 30, 1999, 7-10) which obviously has an effect on the inflammatory process. In normal mice artemisinin and artether affect the immune response ( AF Tawfik et al., Int J Immunopharmacol 12, 1990, 385-389). Artesunate suppressed phagocytosis of peritoneal macrophage in mice ( PY LIN et al, Acta Pharmacol Sin. 16, 1995, 441-444).

The haemolytic effect is well described in the following paper ( A Corpolongo et al., Malaria Journal, 11-91, 2012) 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-inmune 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.

The derivatives of artemisinin are strong peroxides. They create radicals and reactive oxygen species which at high doses might damage cortical and brain stem neurons (G Schmuck et al., Antimicrob Agents and Chemother. 46, 2002, 821-827) and are cytotoxic to many other cells. The genotoxicity of artesunate was was studies in Brazil on mice ( I Aquino et al., Food Chem Toxicol. 2011 Jun;49(6):1335-9.) The 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. (T Mota et al., Environ. Mol. Mutagen., 2011)

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.

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. Nonimmune 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 ( RL Clark et al., Birth Defect Res B Dev Rproduc Toxicol 92, 2011, 52-68). Embryotoxicity is due to dihydroartemisinin, the main metabolite of artesunate and artemether, but not of artemisinin ( S D'Alessandro et al., Toxicology 241, 2007, 66-74)

But none of these hepatotoxic, haemolytic, cytotoxic, immunodepressive effects has ever been observed by drinking Artemisia annua tea.
Several studies ( A Muzemil, PhD thesis, AddisAbeba 2009; JT Mukinda, Thesis, University of Western Cape, 2005; G Chuipet, Thesis, Université des Montagnes, 2012) have confirmed that Artemisia annua tea is completely 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.

Many studies have shown that Artemisia annua stimulates the immune system, increasing for example the monocyte count. ( PE Ogwang et al., Brit J Phar Res., 1, 2011, 124-132) This effect is probably due to other constituents than artemisinin: essential oils, flavonoids, coumarins, polysaccharides, saponins. 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.