Dronedarone, an Amiodarone Analog with Improved Anti-Leishmania mexicana Efficacy

Gustavo Benaim, Paola Casanova, Vanessa Hernandez-Rodriguez, Sheira Mujica-Gonzalez, Nereida Parra-Gimenez, Lourdes Plaza-Rojas, Juan Luis Concepcion, Yi-Liang Liu, Eric Oldfield, Alberto Paniz-Mondolfi, Alirica I. Suarez
  • Antimicrobial Agents and Chemotherapy, February 2014, ASM Journals
  • DOI: 10.1128/aac.01240-13

Dronedarone maintains the antiproliferative effect of amiodarone , and even improve it.

What is it about?

Dronedarone and amiodarone are cationic lipophilic benzofurans used to treat cardiac arrhythmias. They also have activity against the parasitic protozoan Trypanosoma cruzi, the causative agent of Chagas’ disease. They function by disrupting intracellular Ca2_ homeostasis of the parasite and by inhibiting membrane sterol (ergosterol) biosynthesis. Amiodarone also has activity against Leishmania mexicana, suggesting that dronedarone might likewise be active against this organism. This might be of therapeutic interest, since dronedarone is thought to have fewer side effects in humans than does amiodarone. We show here that dronedarone effectively inhibits the growth of L. mexicana promastigotes in culture and, more importantly, has excellent activity against amastigotes inside infected macrophages (the clinically relevant form) without affecting the host cell, with the 50% inhibitory concentrations against amastigotes being 3 orders of magnitude lower than those obtained previously with T. cruzi amastigotes (0.65 nM versus 0.75 _M). As with amiodarone, dronedarone affects intracellular Ca2_ homeostasis in the parasite, inducing an elevation of intracellular Ca2_ levels. This is achieved by rapidly collapsing the mitochondrial membrane potential and inducing an alkalinization of acidocalcisomes at a rate that is faster than that observed with amiodarone. We also show that dronedarone inhibits parasite oxidosqualene cyclase, a key enzyme in ergosterol biosynthesis known to be vital for survival. Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases.

Why is it important?

Our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases.

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http://dx.doi.org/10.1128/aac.01240-13

The following have contributed to this page: Prof. Gustavo Benaim