title: Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole.
abstract: There is no effective treatment for the prevalent chronic form of Chagas' disease in Latin America. Its causative agent, the protozoan parasite Trypanosoma cruzi, has an essential requirement for ergosterol, and ergosterol biosynthesis inhibitors, such as the antifungal drug posaconazole, have potent trypanocidal activity. The antiarrhythmic compound amiodarone, frequently prescribed for the symptomatic treatment of Chagas' disease patients, has also recently been shown to have antifungal activity. We now show here for the first time that amiodarone has direct activity against T. cruzi, both in vitro and in vivo, and that it acts synergistically with posaconazole. We found that amiodarone, in addition to disrupting the parasites' Ca(2+) homeostasis, also blocks ergosterol biosynthesis, and that posaconazole also affects Ca(2+) homeostasis. These results provide logical explanations for the synergistic activity of amiodarone with azoles against T. cruzi and open up the possibility of novel, combination therapy approaches to the treatment of Chagas' disease using currently approved drugs.
authors.affiliation: Laboratorio Química Biológica and Laboratorio de Permeabilidad Iónica, Instituto Venezolano de Investigaciones Científicas, Apartado 21927, Caracas 1020A, Venezuela.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Benaim
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Yael
authors.initials: Y
authors.lastname: Garcia-Marchán
authors.forename: Claudia
authors.initials: C
authors.lastname: Colina
authors.forename: Renee
authors.initials: R
authors.lastname: Lira
authors.forename: Aura R
authors.initials: AR
authors.lastname: Caldera
authors.forename: Gilberto
authors.initials: G
authors.lastname: Payares
authors.forename: Cristina
authors.initials: C
authors.lastname: Sanoja
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Burgos
authors.forename: Annette
authors.initials: A
authors.lastname: Leon-Rossell
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Concepcion
authors.forename: Alejandro G
authors.initials: AG
authors.lastname: Schijman
authors.forename: Mariano
authors.initials: M
authors.lastname: Levin
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
mesh_terms: D000208:Acute Disease; D000638:Amiodarone / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000378:metabolism; D014355:Chagas Disease / Q000188:drug therapy; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004357:Drug Synergism; D004875:Ergosterol / Q000096:biosynthesis; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism; D014709:Vero Cells
chemical_list: D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D000638:Amiodarone; D002118:Calcium; D004875:Ergosterol