1357. A combination of itraconazole and amiodarone is highly effective against Trypanosoma cruzi infection of human stem cell derived cardiomyocytes
Session: Poster Abstract Session: Novel Agents
Friday, October 5, 2018
Room: S Poster Hall
Background: Trypanosoma cruzi is the etiologic agent of Chagas disease, which can result in severe cardiomyopathy. Trypanosoma cruzi is endemic to the Americas, and of particular importance in Latin America. In the USA and other nonendemic countries, rising case numbers have been observed. The only drugs available so far are benznidazole and nifurtimox, which have limited efficacy during chronic infection. We repurposed itraconazole, originally an anti-fungal, in combination with amiodarone, an antiarrhythmic, with the goal to interfere with Tc infection. Both drugs inhibit sterol synthesis, while amiodarone also inhibits calcium metabolism of Trypanosoma cruzi.

Methods: Human pluripotent stem cells (HiPSC) were differentiated to cardiomyocytes (HiPSC-CM). Vero cells or HiPSC-CM were infected with the Trypanosoma cruzi trypomastigotes Y strain in the presence of itraconazole and/or amiodarone. After 48 hours, infection and multiplication were evaluated by Giemsa stain. Benznidazole was used as a reference compound. Cell viability was verified by XTT assay.

Results: Itraconazole and amiodarone showed dose-dependent interference with Trypanosoma cruzi infection of Vero cells or HiPSC-CM. The combination of itraconazole and amiodarone was more potent than the single substances, or benznidazole at therapeutic concentrations, without affecting host cell metabolism. In addition to effects on infection, itraconazole, or amiodarone affected Trypanosoma cruzi multiplication. Here, itraconazole / amiodarone combinations were more potent than either alone, both, in Vero cells, and HiPSC-CM.

Conclusion: Our in vitro data suggest that a combination of itraconazole and amiodarone might serve as an effective new treatment option for Chagas disease, particularly cardiac involvement, in human and animal patients.

Gabriele Sass, PhD1, Roy Madigan, DVM2, Adriana Bozzi, PhD1,3,4,5,6, Nazish Sayed, MD, PhD3,4,5, Joseph Wu, MD3,4,5 and David Stevens, MD1,7, (1)California Institute for Medical Research, San Jose, CA, (2)Animal Hospital of Smithson Valley, Smithson Valley, TX, (3)Department of Medicine, Division of Cardiology, Stanford University, Stanford, CA, (4)Dept. of Radiology, Department of Medicine, Stanford University, Stanford, CA, (5)Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, (6)Centro de Pesquisas René Rachou, FIOCRUZ, Belo Horizonte, Brazil, (7)Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA

Disclosures:

G. Sass, None

R. Madigan, None

A. Bozzi, None

N. Sayed, None

J. Wu, None

D. Stevens, None

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