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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Stimpert, K. K. & Montgomery, S. P. Physician awareness of Chagas disease, USA. Emerg. Infect. Dis. 16, 871–872 (2010).
Hotez, P. J. et al. Chagas disease: “The new HIV/AIDS of the Americas”. PLoS Negl. Trop. Dis. 6, e1498 (2012).
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).
Organización Panamericana de la Salud. Estimación cuantitativa de la Enfermedad de Chagas en las Americas [online], (2006).
Centers for Disease Control and Prevention. Chagas disease in the Americas – 2011 [online], (2011).
Elizari, M. V. & Chiale, P. A. Cardiac arrhythmias in Chagas' Heart Disease. J. Cardiovasc. Electrophysiol. 4, 596–608 (1993).
Bern, C. & Montgomery, S. P. An estimate of the burden of Chagas disease in the United States. Clin. Infect. Dis. 49, 52–54 (2009).
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).
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).
Urbina, J. A. Chemotherapy of Chagas' disease: the how and the why. J. Mol. Med. (Berl.) 77, 332–338 (1999).
Machado, F. S. et al. Pathogenesis of Chagas disease: time to move on. Front. Biosci. (Elite Ed.) 4, 1743–1758 (2012).
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).
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).
Urbina, J. A. & Docampo, R. Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol. 19, 495–501 (2003).
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).
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).
Benaim, G. et al. Amiodarone has intrinsic anti-Trypanosoma cruzi activity and acts synergistically with posaconazole. J. Med. Chem. 49, 892–899 (2006).
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).
Patel, C., Yan, G. X. & Kowey, P. R. Dronedarone. Circulation 120, 636–644 (2009).
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).
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).
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).
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).
Benaim, G. & Garcia, C. R. Targeting calcium homeostasis as the therapy of Chagas' disease and leishmaniasis. Trop. Biomed. 28, 471–481 (2011).
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).
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).
Oyetayo, O. O., Rogers, C. E. & Hofmann, P. O. Dronedarone: a new antiarrhythmic agent. Pharmacotherapy 30, 904–915 (2010).
Hohnloser, S. H. et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med. 360, 668–678 (2008).
Prystowsky, E. N. Atrial fibrillation: dronedarone and amiodarone—the safety versus efficacy debate. Nat. Rev. Cardiol. 7, 5–6 (2010).
Multaq® (dronedarone) package insert (Sanofi-Aventis, 2009).
Dorian, P. Clinical pharmacology of dronedarone: implications for the therapy of atrial fibrillation. J. Cardiovasc. Pharmacol. Ther. 15 (4 Suppl.), 15S–18S (2010).
Kober, L. et al. Increased mortality after dronedarone therapy for severe heart failure. N. Engl. J. Med. 358, 2678–2687 (2008).
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).
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).
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).
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).
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).
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).
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.
The authors declare no competing financial interests.
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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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