Amiodarone and miltefosine act synergistically against Leishmania mexicana and can induce parasitological cure in a murine model of cutaneous leishmaniasis.

Abstract

Leishmaniasis is parasitic disease that is an important problem of public health worldwide. Intramuscularly administered glucantime and pentostam are the most common drugs used for treatment of this disease, but they have significant limitations due to toxicity and increasing resistance. A recent breakthrough has been the introduction of orally administered miltefosine for the treatment of visceral, cutaneous, and mucocutaneous leishmaniasis, but the relative high cost and concerns about teratogenicity have limited the use of this drug. Searching for alternative drugs, we previously demonstrated that the antiarrhythmic drug amiodarone is active against Leishmania mexicana promastigotes and intracellular amastigotes, acting via disruption of intracellular Ca(2+) homeostasis (specifically at the mitochondrion and the acidocalcisomes of these parasites) and through inhibition of the parasite's de novo sterol biosynthesis (X. Serrano-Martín, Y. García-Marchan, A. Fernandez, N. Rodriguez, H. Rojas, G. Visbal, and G. Benaim, Antimicrob. Agents Chemother. 53:1403-1410, 2009). In the present work, we found that miltefosine also disrupts the parasite's intracellular Ca(2+) homeostasis, in this case by inducing a large increase in intracellular Ca(2+) levels, probably through the activation of a plasma membrane Ca(2+) channel. We also investigated the in vitro and in vivo activities of amiodarone and miltefosine, used alone or in combination, on L. mexicana. It was found that the drug combination had synergistic effects on the proliferation of intracellular amastigotes growing inside macrophages and led 90% of parasitological cures in a murine model of leishmaniasis, as revealed by a PCR assay using a novel DNA sequence specific for L. mexicana.

• Authors: Xenón Serrano-Martín, Gilberto Payares, Marisel De Lucca, Juan Carlos Martinez, Alexis Mendoza-León, Gustavo Benaim
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 53 Issue 12 Pg. 5108-13 (Dec 2009) ISSN: 1098-6596 [Electronic] United States
• PMID: 19805563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Phosphorylcholine
• miltefosine
• Amiodarone

Topics

• Amiodarone (therapeutic use)
• Animals
• Antiprotozoal Agents (therapeutic use)
• Cricetinae
• Disease Models, Animal
• Drug Synergism
• Female
• Leishmaniasis, Cutaneous (drug therapy, parasitology)
• Mice
• Phosphorylcholine (analogs & derivatives, therapeutic use)
• Polymerase Chain Reaction