title: In vitro anti-Trypanosoma cruzi activity of dronedarone, a novel amiodarone derivative with an improved safety profile.
abstract: Amiodarone, a commonly used antiarrhythmic, is also a potent and selective anti-Trypanosoma cruzi agent. Dronedarone is an amiodarone derivative in which the 2,5-diiodophenyl moiety of the parental drug has been replaced with an unsubstituted phenyl group aiming to eliminate the thyroid toxicity frequently observed with amiodarone treatment. Dronedarone has been approved by the Food and Drug Administration (FDA), and its use as a safe antiarrhythmic has been extensively documented. We show here that dronedarone also has potent anti-T. cruzi activity, against both extracellular epimastigotes and intracellular amastigotes, the clinically relevant form of the parasite. The 50% inhibitory concentrations against both proliferative stages are lower than those previously reported for amiodarone. The mechanism of action of dronedarone resembles that of amiodarone, as it induces a large increase in the intracellular Ca(2+) concentration of the parasite, which results from the release of this ion from intracellular storage sites, including a direct effect of the drug on the mitochondrial electrochemical potential, and through alkalinization of the acidocalcisomes. Our results suggest a possible future repurposed use of dronedarone for the treatment of Chagas' disease.
authors.affiliation: Instituto de Estudios Avanzados, IDEA, Caracas, Venezuela. gbenaim@idea.gob.ve
authors.forename: Gustavo
authors.initials: G
authors.lastname: Benaim
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hernandez-Rodriguez
authors.forename: Sheira
authors.initials: S
authors.lastname: Mujica-Gonzalez
authors.forename: Lourdes
authors.initials: L
authors.lastname: Plaza-Rojas
authors.forename: May Li
authors.initials: ML
authors.lastname: Silva
authors.forename: Nereida
authors.initials: N
authors.lastname: Parra-Gimenez
authors.forename: Yael
authors.initials: Y
authors.lastname: Garcia-Marchan
authors.forename: Alberto
authors.initials: A
authors.lastname: Paniz-Mondolfi
authors.forename: Graciela
authors.initials: G
authors.lastname: Uzcanga
mesh_terms: D000638:Amiodarone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D014355:Chagas Disease / Q000469:parasitology; D000077764:Dronedarone; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000077764:Dronedarone; D000638:Amiodarone; D002118:Calcium