Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole.
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.
Benaim
Gustavo
G
Laboratorio Química Biológica and Laboratorio de Permeabilidad Iónica, Instituto Venezolano de Investigaciones Científicas, Apartado 21927, Caracas 1020A, Venezuela.
Sanders
John M
JM
Garcia-Marchán
Yael
Y
Colina
Claudia
C
Lira
Renee
R
Caldera
Aura R
AR
Payares
Gilberto
G
Sanoja
Cristina
C
Burgos
Juan Miguel
JM
Leon-Rossell
Annette
A
Concepcion
Juan Luis
JL
Schijman
Alejandro G
AG
Levin
Mariano
M
Oldfield
Eric
E
Urbina
Julio A
JA
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
D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D000638:Amiodarone; D002118:Calcium; D004875:Ergosterol