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Malaria prophylaxis with amiodarone (cordarone).

August 25, 2018 - 17:49 -- Pierre Lutgen

Amiodarone which is used to control irregular heartbeat also has a protective effect in malaria. It triggers eryptosis and the clearance of malaria infected erythrocytes. In Plasmodium berghei infected mice amiodarone injections increased the survival. It is interesting to note that amiodarone is also active against other tropical diseases like Chagas or Leishmaniasis, both in vitro and in vivo, probably by disrupting the parasites' Ca(2+) homeostasis,

    Bobbala D, Alesutan I, Föller M, Protective effect of amiodarone in malaria. Acta Trop 2010. Acta Trop. 2010 Oct;116(1):39-44. doi: 10.1016/j.actatropica.2010.05.005. Epub 2010 May 27.

    JR Piccotti, MS LaGattuta. Induction of apoptosis by cationic amphphilic drugs amiodarone and imipramine. Drugs and Chemical Toxicology, 2005, 28-1, 117-133

    E Lang, F Lang, Triggers, inhibitors, mechanisms and significance of eryptosis: the suicidal erythrocyte death. Hindawi BioMed Research Internat, 2015, ID 513518.

     Benaim G, Sanders JM, Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole. J Med Chem. 2006.

     Gustavo Benaim,Paola Casanova, Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy, 2014 , 58 , 4 Antimicrobial Agents and Chemotherapy p. 2295–2303

One of the side effects of amiodarone is the disruption of the hepatic lipid homeostasis. Amiodarone generates lipid containing vacuoles within the hepatocytes. Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation.

      McCarthy TC1, Pollak PT, Hanniman EA, Sinal CJ. J Pharmacol Exp Ther. 2004 Dec;311(3):864-73. Epub 2004 Jul 20.

Very low density lipoproteins (VLDL), are rapidly cleared from plasma and enter hepatocytes. It has been suggested that remnant lipoproteins are initially captured in the space of Disse and that their subsequent internalization into hepatocytes is mediated by members of the LDL-receptor gene family. Similarly to lipoprotein remnants, malaria sporozoites are removed from the blood circulation by the liver within minutes after injection by Anopheles mosquitoes. The sporozoite's surface is covered by the circumsporozoite protein (CSP), and its region II-plus has. Sporozoites, remnant lipoproteins are cleared from the blood  and compete in vitro and in vivo for binding sites on liver cells.

      Photini Sinnis, Thomas E.Willnow. Remnant Lipoproteins Inhibit Malaria Sporozoite Invasion of Hepatocytes. J Exp Med, 1996, 184, 945-954

      Liane Rabinowich and Oren Shibolet. Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease. Biomed Res Int, 2015. doi: 10.1155/2015/168905

      Begriche K, Massart J, Robin MA, Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol. 2011 Apr;54(4):773-94.

In a previous paper, I described the prophylactic effects on malaria of a ketogenic, high fat diet.

     Pierre Lutgen. New Insights into Malaria Prophylaxis. Pharmacy & Pharmacology International Journal. 2017. Vol 5. Issue 6. And in a document posted on www.malariaworld.org: Pierre Lutgen, Cholesterol, phytosterols and malaria. October 25, 2013.

Plasmodium needs cholesterol, especially HDL, for its development. After a malaria infection the cholesterol load in the human body diminishes. This is confirmed by many studies and a study from India. The interesting feature of the latter is that they describe accurately that this decrease in total cholesterol has nothing to do with fever per se, but is specifically related to the Plasmodium infection. Very strange is also their finding that only HDL and LDL decrease, but that VLDL sharply increases. Previous studies on the lipid profile in malaria had not noticed this change because they only measured LDL and HDL and ignored VLDL. But this VLDL increase is poorly understood. It is possible that at the release of the sporozoites from the liver at the same time VLDL is released. The fact that this increase is noticed on day one of the erythrocyte invasion by merozoites pleads in favor of this hypothesis.

      B K. Kullu, Chakradhar Majhi, Lipid profiles among Plasmodium falciparum infected, non malarial febrile patients and volunteers. Int J Adv Med. 2018 Jun;5(3):556-560