1. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole.
- Author
-
Benaim G, Sanders JM, Garcia-Marchán Y, Colina C, Lira R, Caldera AR, Payares G, Sanoja C, Burgos JM, Leon-Rossell A, Concepcion JL, Schijman AG, Levin M, Oldfield E, and Urbina JA
- Subjects
- Acute Disease, Amiodarone chemistry, Amiodarone therapeutic use, Animals, Calcium metabolism, Chagas Disease drug therapy, Chlorocebus aethiops, Crystallography, X-Ray, Drug Synergism, Ergosterol biosynthesis, Intramolecular Transferases antagonists & inhibitors, Intramolecular Transferases chemistry, Mice, Models, Molecular, Molecular Structure, Triazoles chemistry, Triazoles therapeutic use, Trypanocidal Agents chemistry, Trypanocidal Agents therapeutic use, Trypanosoma cruzi metabolism, Vero Cells, Amiodarone pharmacology, Triazoles pharmacology, Trypanocidal Agents pharmacology, Trypanosoma cruzi drug effects
- 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.
- Published
- 2006
- Full Text
- View/download PDF