Gustavo Benaim*, Alberto E. Paniz-Mondolfi and Emilia Mia Sordillo Pages 1825 - 1833 ( 9 )
The repurposing or repositioning of previously-approved drugs has become an accepted strategy for the expansion of the pharmacopeia for neglected diseases. Accordingly, amiodarone, an inexpensive and extensively- used class III antiarrhythmic has been proposed as a treatment for Chagas’ disease and leishmaniasis. Amiodarone has a potent trypanocidal and leishmanicidal action, mainly acting through the disruption of parasite intracellular Ca2+ homeostasis, which is a recognized target of different drugs that have activity against trypanosomatids. Amiodarone collapses the mitochondrial electrochemical potential (Δφm) and induces the rapid alkalinization of parasite acidocalcisomes, driving a large increase in the intracellular Ca2+ concentration. Amiodarone also inhibits oxidosqualene cyclase activity, a key enzyme in the ergosterol synthesis pathway that is essential for trypanosomatid survival. In combination, these three effects lead to parasite death. Dronedarone, a drug synthesized to minimize some of the adverse effects of amiodarone, displays trypanocidal and leishmanicidal activity through the same mechanisms, but curiously, being more potent on Leishmaniasis than its predecessor. In vitro studies suggest that other recently-synthesized benzofuran derivatives can act through the same mechanisms, and produce similar effects on different trypanosomatid species. Recently, the combination of amiodarone and itraconazole has been used successfully to treat 121 dogs naturally-infected by T. cruzi, strongly supporting the potential therapeutic use of this combination against human trypanosomatid infections.
Amiodarone, dronedarone, benzofuran derivatives, calcium, Trypanosoma cruzi, Chagas disease, Leishmaniasis.
Instituto de Estudios Avanzados (IDEA) , Caracas, Instituto de Estudios Avanzados (IDEA) , Caracas, Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York