Experimental Combination Therapy with Amiodarone and Low-Dose Benznidazole in a Mouse Model of Trypanosoma cruzi Acute Infection

Barbosa, Juliana M. C.; Rezende, Yasmin Pedra; Melo, Tatiana G.; Oliveira, Gabriel de; Cascabulho, Cynthia Machado; Pereira, Evelyn Nunes Goulart da Silva; Daliry, Anissa; Salomão, Kelly

doi:10.1128/spectrum.01852-21

Cited by 7 publications

(7 citation statements)

References 66 publications

(78 reference statements)

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“…When we tested both compounds in vivo in the well-established and standardized bioluminescent imaging (BLI) model (37), no efficacy was observed either in the acute or chronic model of T. cruzi. These data are in sharp contrast to former studies claiming a potential benefit of the treatment with these compounds, alone, or in combination with azoles in murine or canine models of T. cruzi infection (25,38,39).…”

Section: Discussioncontrasting

confidence: 99%

“…Amiodarone and dronedarone were prepared for administration in an aqueous suspension vehicle containing 0.5% (w/v) hydroxypropyl methylcellulose and 0.4% (v/v) Tween 80. The dosing regimens were selected based on previously published in vivo work (25,38). Drugs were administered by oral gavage (adjusted by weight), and vehicle only was administered to control mice.…”

Section: Mice and Parasitesmentioning

confidence: 99%

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Preclinical data do not support the use of amiodarone or dronedarone as antiparasitic drugs for Chagas disease at the approved human dosing regimen

Francisco,

Chen,

Wang

et al. 2023

Front. Trop. Dis

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The repurposing of approved drugs is an appealing method to fast-track the development of novel therapies for neglected diseases. Amiodarone and dronedarone, two approved antiarrhythmic agents, have been reported to have potential for the management of Chagas disease patients displaying symptomatic heart pathology. More recently, it has been suggested that both molecules not only have an antiarrhythmic effect, but also have trypanocidal activity against Trypanosoma cruzi, the causative agent of Chagas disease. In this work, we assessed the in vitro activity of these compounds against T. cruzi, the in vivo pharmacokinetics, and pharmacodynamics, to determine the potential for repurposing these drugs as therapies for Chagas disease. Based on these results, we were unable to reproduce the in vitro potencies of amiodarone and dronedarone described in the literature, and both drugs were found to be inactive or cytotoxic against a variety of different mammalian cell lines. The evaluation of in vivo efficacy in a bioluminescent murine model of T. cruzi did not show antiparasitic activity at the highest tolerated dose tested. While the potential of amiodarone and dronedarone as antiarrhythmic agents in Chagas cardiomyopathic patients cannot be completely excluded, a trypanocidal effect in patients treated with these two drugs appears unlikely.

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Section: Discussioncontrasting

confidence: 99%

Section: Mice and Parasitesmentioning

confidence: 99%

Preclinical data do not support the use of amiodarone or dronedarone as antiparasitic drugs for Chagas disease at the approved human dosing regimen

Francisco,

Chen,

Wang

et al. 2023

Front. Trop. Dis

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“…As a perspective, it would be interesting to evaluate the parameters in a more advanced chronic stage of ChD, in which it would be possible to analyze the drug’s effect in the long term. On the other hand, nitazoxanide could be used in combination with benznidazole to improve its trypanocidal effectiveness, as noted by several authors when combining different drugs with benznidazole [ 22 , 23 , 31 , 43 , 44 , 45 , 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Nitazoxanide: A Drug Repositioning Compound with Potential Use in Chagas Disease in a Murine Model

et al. 2023

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Chagas disease (ChD), caused by Trypanosoma cruzi, is the most serious parasitosis in the western hemisphere. Benznidazole and nifurtimox, the only two trypanocidal drugs, are expensive, difficult to obtain, and have severe side effects. Nitazoxanide has shown to be effective against protozoa, bacteria, and viruses. This study aimed to evaluate the nitazoxanide efficacy against the Mexican T. cruzi Ninoa strain in mice. Infected animals were orally treated for 30 days with nitazoxanide (100 mg/kg) or benznidazole (10 mg/kg). The clinical, immunological, and histopathological conditions of the mice were evaluated. Nitazoxanide- or benznidazole-treated mice had longer survival and less parasitemia than those without treatment. Antibody production in the nitazoxanide-treated mice was of the IgG1-type and not of the IgG2-type as in the benznidazole-treated mice. Nitazoxanide-treated mice had significantly high IFN-γ levels compared to the other infected groups. Serious histological damage could be prevented with nitazoxanide treatment compared to without treatment. In conclusion, nitazoxanide decreased parasitemia levels, indirectly induced the production of IgG antibodies, and partially prevented histopathological damage; however, it did not show therapeutic superiority compared to benznidazole in any of the evaluated aspects. Therefore, the repositioning of nitazoxanide as an alternative treatment against ChD could be considered, since it did not trigger adverse effects that worsened the pathological condition of the infected mice.

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“… 155 Its combination with benznidazole in mouse models of infection also improved electrocardiographic markers of cardiac damage and reduced levels of pro-inflammatory markers and collagen deposition. 156 Its use in naturally infected dogs led to improved survival. 157 However, a recent meta-analysis of patients with chronic Chagas disease who received amiodarone confirmed its antiarrhythmic benefits, but did not find any evidence of reductions in mortality or hospitalizations.…”

Section: Targeting the Pathogenesis Of Chronic Damage As A Complement...mentioning

confidence: 99%

State-of-the-Art in the Drug Discovery Pathway for Chagas Disease: A Framework for Drug Development and Target Validation

Gabaldón-Figueira,

Martinez-Peinado,

Escabia

et al. 2023

RRTM

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Chagas disease is the most important protozoan infection in the Americas, and constitutes a significant public health concern throughout the world. Development of new medications against its etiologic agent, Trypanosoma cruzi , has been traditionally slow and difficult, lagging in comparison with diseases caused by other kinetoplastid parasites. Among the factors that explain this are the incompletely understood mechanisms of pathogenesis of T. cruzi infection and its complex set of interactions with the host in the chronic stage of the disease. These demand the performance of a variety of in vitro and in vivo assays as part of any drug development effort. In this review, we discuss recent breakthroughs in the understanding of the parasite’s life cycle and their implications in the search for new chemotherapeutics. For this, we present a framework to guide drug discovery efforts against Chagas disease, considering state-of-the-art preclinical models and recently developed tools for the identification and validation of molecular targets.

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Experimental Combination Therapy with Amiodarone and Low-Dose Benznidazole in a Mouse Model of Trypanosoma cruzi Acute Infection

Cited by 7 publications

References 66 publications

Preclinical data do not support the use of amiodarone or dronedarone as antiparasitic drugs for Chagas disease at the approved human dosing regimen

Preclinical data do not support the use of amiodarone or dronedarone as antiparasitic drugs for Chagas disease at the approved human dosing regimen

Nitazoxanide: A Drug Repositioning Compound with Potential Use in Chagas Disease in a Murine Model

State-of-the-Art in the Drug Discovery Pathway for Chagas Disease: A Framework for Drug Development and Target Validation

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