The emerging role of amiodarone and dronedarone in Chagas disease

Abstract

Chagas disease has emerged as an important health problem in the Americas and, with globalization, in other parts of the world. Drug therapy for this parasitic infection has remained largely ineffective, especially in chronic stages of the disease. However, developments in experimental therapy might signal an important advance for the management of patients with Chagas disease. Herein, we review studies on the potential use of the benzofuran derivatives amiodarone and dronedarone in patients with Chagas disease. These agents have a dual role, not only as primary antiarrhythmic drugs, but also as antiparasitic agents. We believe that this 'kill two birds with one stone' approach represents a new tactic for the treatment of Chagas disease using currently approved drugs.

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Figure 1
Figure 2: Amiodarone disrupts intracellular Ca2+ homeostasis in T. cruzi.
Figure 3: Effects of amiodarone on the ultrastructure of intracellular T. cruzi (Y strain) amastigotes.
Figure 4: Comparison of amiodarone and dronedarone structure and function.

References

  1. 1

    Stimpert, K. K. & Montgomery, S. P. Physician awareness of Chagas disease, USA. Emerg. Infect. Dis. 16, 871–872 (2010).

    Article  Google Scholar 

  2. 2

    Hotez, P. J. et al. Chagas disease: “The new HIV/AIDS of the Americas”. PLoS Negl. Trop. Dis. 6, e1498 (2012).

    Article  Google Scholar 

  3. 3

    Schmunis, G. A. Epidemiology of Chagas disease in non-endemic countries: the role of international migration. Mem. Inst. Oswaldo Cruz 102 (Suppl. 1), 75–85 (2007).

    Article  Google Scholar 

  4. 4

    Organización Panamericana de la Salud. Estimación cuantitativa de la Enfermedad de Chagas en las Americas [online], (2006).

  5. 5

    Centers for Disease Control and Prevention. Chagas disease in the Americas – 2011 [online], (2011).

  6. 6

    Elizari, M. V. & Chiale, P. A. Cardiac arrhythmias in Chagas' Heart Disease. J. Cardiovasc. Electrophysiol. 4, 596–608 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Bern, C. & Montgomery, S. P. An estimate of the burden of Chagas disease in the United States. Clin. Infect. Dis. 49, 52–54 (2009).

    Article  Google Scholar 

  8. 8

    Rassi, A. Jr, Rassi, A. & Marin-Neto, J. A. Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Mem. Inst. Oswaldo Cruz. 10, 152–158 (2009).

    Article  Google Scholar 

  9. 9

    Muratore, C. A. & Baranchuk, A. Current and emerging therapeutic options for the treatment of chronic chagasic cardiomyopathy. Vasc. Health Risk Manag. 6, 593–601 (2010).

    CAS  Article  Google Scholar 

  10. 10

    Urbina, J. A. Chemotherapy of Chagas' disease: the how and the why. J. Mol. Med. (Berl.) 77, 332–338 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Machado, F. S. et al. Pathogenesis of Chagas disease: time to move on. Front. Biosci. (Elite Ed.) 4, 1743–1758 (2012).

    Article  Google Scholar 

  12. 12

    Tarleton, R. L., Zhang, L. & Downs M. O. “Autoimmune rejection” of neonatal heart transplants in experimental Chagas' disease is a parasite-specific response to infected host tissue. Proc. Natl Acad. Sci. USA 94, 3932–3937 (1997).

    CAS  Article  Google Scholar 

  13. 13

    Marin-Neto, J. A. et al. Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas' cardiomyopathy: the BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT). Am. Heart J. 156, 37–43 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Urbina, J. A. & Docampo, R. Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol. 19, 495–501 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Cardinalli-Neto, A., Greco, O. T. & Bestetti, R. Automatic implantable cardioverter-defibrillators in Chagas' heart disease patients with malignant ventricular arrhythmias. Pacing Clin. Electrophsiol. 29, 467–470 (2006).

    Article  Google Scholar 

  16. 16

    Paniz Mondolfi, A. E., Pérez-Álvarez, A. M., Lanza, G., Márquez, E. & Concepción, J. L. Amiodarone and itraconazole: a rational therapeutic approach for the treatment of chronic Chagas' disease. Chemotherapy 55, 228–233 (2009).

    CAS  Article  Google Scholar 

  17. 17

    Benaim, G. et al. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole. J. Med. Chem. 49, 892–899 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Pinazo, M. et al. Successful treatment with posaconazole of a patient with chronic Chagas disease and systemic lupus erythematosus. Am. J. Trop. Med. Hyg. 82, 583–587 (2010).

    CAS  Article  Google Scholar 

  19. 19

    Patel, C., Yan, G. X. & Kowey, P. R. Dronedarone. Circulation 120, 636–644 (2009).

    CAS  Article  Google Scholar 

  20. 20

    Haedo, A. H. et al. Comparative antiarrhythmic efficacy of verapamil, 17-monochloracetylamaline, mexiletine, and amiodarone in patients with severe chagasic myocarditis: relation with the underlying arrhythmogenic mechanisms. J. Am. Coll. Cardiol. 7, 1114–1120 (1986).

    CAS  Article  Google Scholar 

  21. 21

    Rosenbaum, M. et al. Comparative multicenter clinical study of flecainide and amiodarone in the treatment of ventricular arrhythmias associated with chronic Chagas cardiomyopathy [Spanish]. Arch. Inst. Cardiol. Mex. 57, 325–330 (1987).

    CAS  PubMed  Google Scholar 

  22. 22

    Chiale, P. A. et al. Efficacy of amiodarone during long-term treatment of malignant ventricular arrhythmias in patients with chronic chagasic myocarditis. Am. Heart J. 107, 656–665 (1984).

    CAS  Article  Google Scholar 

  23. 23

    Benaim, G. et al. In vitro anti-Trypanosoma cruzi activity of dronedarone, a novel amiodarone derivative with an improved safety profile. Antimicrob. Agents Chemother. 56, 3720–3725 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Benaim, G. & Garcia, C. R. Targeting calcium homeostasis as the therapy of Chagas' disease and leishmaniasis. Trop. Biomed. 28, 471–481 (2011).

    PubMed  Google Scholar 

  25. 25

    Veiga-Santos, P. et al. Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int. J. Antimicrob. Agents 40, 61–71 (2012).

    CAS  Article  Google Scholar 

  26. 26

    Adesse, D., Azzam, E. M., Meirelles, M. de. N. L., Urbina, J. A. & Garzoni, L. R. Amiodarone inhibits Trypanosoma cruzi infection and promotes cardiac cell recovery with gap junction and cytoskeleton reassembly in vitro. Antimicrob. Agents Chemother. 55, 203–210 (2011).

    CAS  Article  Google Scholar 

  27. 27

    Oyetayo, O. O., Rogers, C. E. & Hofmann, P. O. Dronedarone: a new antiarrhythmic agent. Pharmacotherapy 30, 904–915 (2010).

    CAS  Article  Google Scholar 

  28. 28

    Hohnloser, S. H. et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 360, 668–678 (2008).

    Article  Google Scholar 

  29. 29

    Prystowsky, E. N. Atrial fibrillation: dronedarone and amiodarone—the safety versus efficacy debate. Nat. Rev. Cardiol. 7, 5–6 (2010).

    CAS  Article  Google Scholar 

  30. 30

    Multaq® (dronedarone) package insert (Sanofi-Aventis, 2009).

  31. 31

    Dorian, P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J. Cardiovasc. Pharmacol. Ther. 15 (4 Suppl.), 15S–18S (2010).

    CAS  Article  Google Scholar 

  32. 32

    Kober, L. et al. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 358, 2678–2687 (2008).

    Article  Google Scholar 

  33. 33

    Franco-Paredes, C., Bottazzi, M. E. & Hotez, P. J. The unfinished public health agenda of Chagas disease in the era of globalization. PLoS Negl. Trop. Dis. 3, e470 (2009).

    Article  Google Scholar 

  34. 34

    Yun, O. et al. Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Médicins Sans Frontiéres. PLoS Negl. Trop. Dis. 3, e488 (2009).

    Article  Google Scholar 

  35. 35

    Bestetti, R. B. et al. Effects of B-Blockers on outcome of patients with Chagas' cardiomyopathy with chronic heart failure. Int. J. Cardiol. 151, 205–208 (2011).

    Article  Google Scholar 

  36. 36

    TDR. Nine projects to find new solutions to dengue and Chagas disease: An eco-bio-social approach in Latin America and the Caribbean [online], (2011).

  37. 37

    Ribeiro, I. et al. New, improved treatments for Chagas disease: from the R&D pipeline to the patients. PLoS Negl. Trop. Dis. 3, e484 (2009).

    Article  Google Scholar 

  38. 38

    Mathers, C. D., Ezzati, M. & Lopez, A. D. Measuring the burden of neglected tropical diseases: the global burden of disease framework. PLoS Negl. Trop. Dis. 1, e114 (2007).

    Article  Google Scholar 

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Acknowledgements

This work was supported by grant 2011000884 from the Consejo Nacional de Investigaciones Científicas y Tecnológicas (FONACIT), Venezuela (to G. Benaim), grant PI 03-00-7380-2008/2 from the Consejo de Desarrollo Científico y Humanístico from the Universidad Central de Venezuela (C.D.C.H.-U.C.V), Venezuela (to G. Benaim), and grant IVSS-430-06-14/05/2007 from the Instituto Venezolano de los Seguros Sociales, Venezuela (to A. E. Paniz Mondolfi). The authors would like to thank Dr Emilia Mia Sordillo (Senior Attending Physician, Division of Infectious Diseases and Epidemiology, Department of Medicine, St Luke's-Roosevelt Hospital Center, New York, NY, USA) for critically reviewing the manuscript.

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Benaim, G., Paniz Mondolfi, A. The emerging role of amiodarone and dronedarone in Chagas disease. Nat Rev Cardiol 9, 605–609 (2012). https://doi.org/10.1038/nrcardio.2012.108

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