{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:06:57Z","timestamp":1789207617972,"version":"build-2803163510"},"reference-count":24,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2009,12,1]],"date-time":"2009-12-01T00:00:00Z","timestamp":1259625600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>Leishmania mexicana<\/jats:italic>\n                    promastigotes and intracellular amastigotes, acting via disruption of intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis (specifically at the mitochondrion and the acidocalcisomes of these parasites) and through inhibition of the parasite's de novo sterol biosynthesis (X. Serrano-Marti\u0301n, Y. Garci\u0301a-Marchan, A. Fernandez, N. Rodriguez, H. Rojas, G. Visbal, and G. Benaim, Antimicrob. Agents Chemother.\n                    <jats:bold>53:<\/jats:bold>\n                    1403-1410, 2009). In the present work, we found that miltefosine also disrupts the parasite's intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis, in this case by inducing a large increase in intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels, probably through the activation of a plasma membrane Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel. We also investigated the in vitro and in vivo activities of amiodarone and miltefosine, used alone or in combination, on\n                    <jats:italic>L. mexicana<\/jats:italic>\n                    . 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\n                    <jats:italic>L. mexicana<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1128\/aac.00505-09","type":"journal-article","created":{"date-parts":[[2009,10,5]],"date-time":"2009-10-05T21:21:07Z","timestamp":1254777667000},"page":"5108-5113","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":53,"title":["Amiodarone and Miltefosine Act Synergistically against\n                    <i>Leishmania mexicana<\/i>\n                    and Can Induce Parasitological Cure in a Murine Model of Cutaneous Leishmaniasis"],"prefix":"10.1128","volume":"53","author":[{"given":"Xeno\u0301n","family":"Serrano-Marti\u0301n","sequence":"first","affiliation":[{"name":"Centro de Biociencias y Medicina Molecular, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela"},{"name":"Instituto de Biologi\u0301a Experimental, Facultad de Ciencias, Universidad Central de Venezuela (UCV), Caracas, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilberto","family":"Payares","sequence":"additional","affiliation":[{"name":"Instituto de Biologi\u0301a Experimental, Facultad de Ciencias, Universidad Central de Venezuela (UCV), Caracas, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisel","family":"De Lucca","sequence":"additional","affiliation":[{"name":"Centro de Biociencias y Medicina Molecular, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Martinez","sequence":"additional","affiliation":[{"name":"Centro de Biociencias y Medicina Molecular, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Mendoza-Leo\u0301n","sequence":"additional","affiliation":[{"name":"Instituto de Biologi\u0301a Experimental, Facultad de Ciencias, Universidad Central de Venezuela (UCV), Caracas, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Benaim","sequence":"additional","affiliation":[{"name":"Centro de Biociencias y Medicina Molecular, Instituto de Estudios Avanzados (IDEA), Caracas, Venezuela"},{"name":"Instituto de Biologi\u0301a Experimental, Facultad de Ciencias, Universidad Central de Venezuela (UCV), Caracas, Venezuela"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"89","year":"1996","unstructured":"Benaim, G. 1996. Intracellular calcium signaling and regulation in Leishmania, p. 89-106. In F. Tapia, G. Caceres-Dittmar, and M. A. Sanchez (ed.), Molecular and immune mechanism in the pathogenesis of cutaneous leishmania. R. G. Landes, Co., Medical Intelligence Unit, Austin, TX.","journal-title":"Molecular and immune mechanism in the pathogenesis of cutaneous leishmania"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm050691f"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2005.02.014"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trstmh.2006.03.009"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)83641-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.22.5.743"},{"key":"e_1_3_2_8_2","first-page":"4027","volume":"19","year":"1999","unstructured":"Henke, J., J. Engelmann, B. Kutscher, G. Nssner, J. Engel, R. Voegeli, and D. Leibfritz. 1999. Changes of intracellular calcium, fatty acids and phospholipids during miltefosine-induced apoptosis monitored by fluorescence- and 13C NMR-spectroscopy. Anticancer Res.19:4027-4032.","journal-title":"Anticancer Res."},{"key":"e_1_3_2_9_2","first-page":"537","volume":"47","year":"2001","unstructured":"Lira, R., L. M. Contreras, R. Santa-Rita, and J. A. Urbina. 2001. Mechanism of action of antiproliferative alkyl-lysophospholipids against the protozoan parasite Trypanosoma cruzi. Potentiation ofin vitro activity by the sterol biosynthesis inhibitor ketoconazole. J. Antimicrob. Chemother. 47:537-546.","journal-title":"Potentiation of"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-6851(00)00278-4"},{"key":"e_1_3_2_11_2","first-page":"1857","volume":"15","year":"2006","unstructured":"Mehta, A., and C. Shaha. 2006. Mechanism of metalloid-induced death in Leishmania spp.: role of iron, reactive oxygen species, Ca2+, and glutathione. Free Radic. Biol. 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