Artesunate IV injections may kill

Oral monotherapy has been banned by WHO, but parenteral monotherapy therapy in accordance with the 2010 World Health Organization Guidelines is again recommended in case of severe malaria. Artemisinin derivatives not only lead to resistance, widespread in Africa now. N Van Hong and U. d’Alessandro describe the case of a man with severe malaria who does not respond to intravenous artesunate. Van Hong N, Amambua-Ngwa A, Tuan NQ, Cuong DD, Giang NTH, Van Dung N, U d’Alessandro. Severe malaria not responsive to artemisinin derivatives in man returning from Angola to Vietnam. Emerg Infect Dis 2014 Jul.doi.org/10.3201/eid2007.140155 A recent paper from Germany describes post-treatment haemolysis by intravenous IV artesunate for three patients with pararasitaemia. The effect appears 2-3 weeks after the treatment. Thierry Rolling, Stefan Schmiedel, Dominic Wichmann, Dieter Wittkopf, Gerd-Dieter Burchard and Jakob P Cramer. Post-treatment haemolysis in severe imported malaria after intravenous artesunate: case report of three patients with hyperparasitaemia. Malaria Journal201211:169DOI: 10.1186/1475-2875-11-169 Anemia after IV artesunate treatment is also reported in France. Martin Danis, Marc Thellier, Le paludisme grave à P. falciparum en France, 2000-2011 : évolution épidémiologique et nécessité d’une nouvelle prise en charge thérapeutique. Bull Acad Nat Méd 3, 699-716, 2013 Artesunate is not licensed in Europe but has been available in France since May 2011 through patient program controlled by the French Agency for Drug Safety [ANSM]. The first 99 patients treated with artesunate up to September 2012 experienced satisfactory efficacy and tolerability. Delayed, sometimes persistent anemia was observed in 29% of the patients. This unexpected adverse effect requires further investigation. IV artesunate is now recommended as the first-line treatment for severe falciparum malaria in France. This is close to the average figure reported for Europe : 6 patients out of 25 travelers IV treated at 7 centers in Europe Thomas Zoller, Thomas Junghanss, Annette Kapaun, Ida Gjørup, Joachim Richter, Intravenous Artesunate for Severe Malaria in Travelers, Europe. Emerg Infect Dis. 2011 May; 17(5): 771–777. doi: 10.3201/eid1705.101229 The letal effect of iv injections of artesunate has also been documented in animal trials against Fasciola hepatica. 3 sheep out of 6 24-72 post-treatment showing tremors, lethargy and reduced rumination. Keiser J, Veneziano V, Cringoli G. Anthelmintic activity of artesunate against Fasciola hepatica in naturally infected sheep. Res Vet Sci 2009 Jun 4 Severe allergies to artesunate have been documented Leonardi E, Gilvary G, White NJ, Nosten F. Severe allergic reactions to oral artesunate: a report of two cases. Trans R Soc Trop Med Hyg. 2001 Mar-Apr;95(2):182-3. Krippner R, Staples J. Suspected allergy to artemether-lumefantrine treatment of malaria. J Travel Med. 2003 Sep-Oct; 10(5):303-5. Artemisinin derivatives not only lead to resistance, widespread in Africa now, but also to hyaemolytic anemia. This has been described in a recent review paper. K Rehman, F Lorsch, P Kresmner. Hemolysis associated with the treatment of malaria with artemisinin derivatives : a systematic review of current evidence. Int J Infect Dis, 2014, vol 29 268-273 A recent paper describes the case of a man with severe malaria who does not respond to intravenous artesunate. A paper from Germany describes post-treatment haemolysis by intravenous artesunate for three patients with pararasitaemia. The effect appears 2-3 weeks after the treatment. Nguyen Van Hong, Alfred Amambua-Ngwa, Nguyen Quang Tuan, Do Duy Cuong, Nguyen Thi Huong Giang, Nguyen Van Dung, Ta Thi Tinh, Nguyen Van Tien, Bui Quang Phuc, Tran Thanh Duong, Anna Rosanas-Urgell, Umberto D’Alessandro, Jean-Pierre Van Geertruyden, and Annette Erhart. Severe Malaria Not Responsive to Artemisinin Derivatives in Man Returning from Angola to Vietnam. Emerg Infect Dis. 2014 Jul; 20(7): 1207–1210. doi: 10.3201/eid2007.140155 Thierry Rolling, Stefan Schmiedel, Dominic Wichmann, Dieter Wittkopf, Gerd-Dieter Burchard and Jakob P Cramer. Post-treatment haemolysis in severe imported malaria after intravenous artesunate: case report of three patients with hyperparasitaemia. Malaria Journal 2012 11:169. DOI: 10.1186/1475-2875-11-169 Several other research teams have seen strong evidence for the same haemolytic anemia caused by IV artesunate. Annemarie R Kreeftmeijer-Vegter, Treatment outcome of intravenous artesunate in patients with severe malaria in the Netherlands and Belgium . Malaria Journal, 11:102 doi:10.1186/1475-2875-11-102, 2012. Pietro Caramello, Severe malaria, artesunate and haemolysis, Journal of Antimicrobial Chemotherapy Volume 67, Issue 8 Pp. 2053-2054. 2012. S Kano, Artemisin-based combination therapies and their introduction in Japan, Infect Chemother 16(6) : 375-382, 2010. Further studies are necessary to assess the pathophysiological background of this complication. Most antimalarials have a hemolytic effect. The strongest are known for quinine, chloroquine and primaquine. At high doses Fansidar® and Coartem® also cause significant hemolysis. Anaba FC, Ahiante BO, Pepple DJ. In vitro hemolytic effect of sulfadoxine/pyrimethamine and artemether/lumefantrine on malaria parasitized erythrocytes of female patients. Pak J Pharm Sci. 2012 Oct;25(4):851-5. A document in Scientific American (June 2014) describes the activities of MVV Medecines for Malaria Ventures, a « non profit » organization located at Geneva. It is surprising to learn that they sell Artesunate in monotherapy for intravenous injection at high doses ; in cooperation with WHO and Médecins sans Frontières. Artemisia plants and their flavonoids however have an anti-haemolytic effect. Naqinezhad A1, Nabavi SM, Nabavi SF, Ebrahimzadeh MA Antioxidant and antihemolytic activities of flavonoid rich fractions of Artemisia tschernieviana Besser. Eur Rev Med Pharmacol Sci. 2012 Jul; 16 Suppl 3:88-94.