Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi
| Autor: | Ranae M. Ranade, Frederick S. Buckner, Robert Don, Joseph D. Planer, Jennifer A. Arif, Matthew A. Hulverson |
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| Rok vydání: | 2013 |
| Předmět: |
Drug
Chagas disease Posaconazole lcsh:Arctic medicine. Tropical medicine lcsh:RC955-962 media_common.quotation_subject Trypanosoma cruzi Antifungal drug Parasitemia Biology Pharmacology Mice parasitic diseases medicine Medicine and Health Sciences Animals Clemastine media_common Mice Inbred BALB C lcsh:Public aspects of medicine Public Health Environmental and Occupational Health Biology and Life Sciences lcsh:RA1-1270 Drug Synergism Triazoles medicine.disease biology.organism_classification Trypanocidal Agents 3. Good health Drug Combinations Chemistry Infectious Diseases Pyrimethamine Immunology Physical Sciences Female medicine.drug Research Article |
| Zdroj: | PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 8, Iss 7, p e2977 (2014) |
| ISSN: | 1935-2735 |
| Popis: | 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. Author Summary Chronic infection with Trypanosoma cruzi causes progressive damage to the heart and other organs that is fatal in about 30% of cases. Known as Chagas disease, this is a major public health problem in Latin America. The existing medicines were developed over forty years ago and are not widely used because of toxicity and unreliable effectiveness. To discover better treatments, we screened a collection of existing drugs for growth inhibitory activity on Trypanosoma cruzi. Several dozen orally administered drugs were discovered, but when used by themselves they were not strong enough to cure the infection in an animal model. We tested a set of 24 of these drugs in every two-way combination and identified eight synergistic partners. At least two of these combinations were able to substantially lower parasite levels in the mouse model of Trypanosoma cruzi infection. Thus, finding pairs of FDA-approved drugs that can be used in combination may be a pragmatic and effective strategy for designing new therapies for Chagas disease. |
| Databáze: | OpenAIRE |
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