Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi.
An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to addres...
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ftdoajarticles:oai:doaj.org/article:ba693335c824477fa3bbab1573a1a19d 2023-05-15T15:15:42+02:00 Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. Joseph D Planer Matthew A Hulverson Jennifer A Arif Ranae M Ranade Robert Don Frederick S Buckner 2014-07-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002977 https://doaj.org/article/ba693335c824477fa3bbab1573a1a19d EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4102417?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002977 https://doaj.org/article/ba693335c824477fa3bbab1573a1a19d PLoS Neglected Tropical Diseases, Vol 8, Iss 7, p e2977 (2014) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2014 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002977 2022-12-31T00:49:30Z An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM), and an antifolate drug (pyrimethamine, EC50 of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 8 7 e2977 |
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Directory of Open Access Journals: DOAJ Articles |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Joseph D Planer Matthew A Hulverson Jennifer A Arif Ranae M Ranade Robert Don Frederick S Buckner Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM), and an antifolate drug (pyrimethamine, EC50 of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease. |
format |
Article in Journal/Newspaper |
author |
Joseph D Planer Matthew A Hulverson Jennifer A Arif Ranae M Ranade Robert Don Frederick S Buckner |
author_facet |
Joseph D Planer Matthew A Hulverson Jennifer A Arif Ranae M Ranade Robert Don Frederick S Buckner |
author_sort |
Joseph D Planer |
title |
Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. |
title_short |
Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. |
title_full |
Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. |
title_fullStr |
Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. |
title_full_unstemmed |
Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. |
title_sort |
synergy testing of fda-approved drugs identifies potent drug combinations against trypanosoma cruzi. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2014 |
url |
https://doi.org/10.1371/journal.pntd.0002977 https://doaj.org/article/ba693335c824477fa3bbab1573a1a19d |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 8, Iss 7, p e2977 (2014) |
op_relation |
http://europepmc.org/articles/PMC4102417?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002977 https://doaj.org/article/ba693335c824477fa3bbab1573a1a19d |
op_doi |
https://doi.org/10.1371/journal.pntd.0002977 |
container_title |
PLoS Neglected Tropical Diseases |
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8 |
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7 |
container_start_page |
e2977 |
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