Hepatic changes by benznidazole in a specific treatment for Chagas disease

Pavan, Tycha Bianca Sabaini; Silva, Jamiro Wanderley da; Martins, Luíz Cláudio; Costa, Sandra Cecı́lia Botelho; Almeida, Eros Antônio de

doi:10.1371/journal.pone.0200707

Cited by 12 publications

(5 citation statements)

References 24 publications

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“…The elevated ALT values decreased for most animals during the recovery phases of the study (Supplemental Table 4). Similar ALT changes have been noted in humans treated with 5-10 mg/kg/day [23]. No other serum chemistry abnormalities and no hematological changes were consistently identified in the treated macaques (Supplemental Tables 4, 5).…”

Section: Resultssupporting

confidence: 76%

Frequency variation and dose modification of benznidazole administration for the treatment ofTrypanosoma cruziinfection in mice, dogs and non-human primates

Tarleton

Bustamante

White

et al. 2023

Preprint

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Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and non-human primates (NHP). Collectively these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ~2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.

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Section: Resultssupporting

confidence: 76%

Frequency variation and dose modification of benznidazole administration for the treatment ofTrypanosoma cruziinfection in mice, dogs and non-human primates

Tarleton

Bustamante

White

et al. 2023

Preprint

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“…Symptoms of BZN-induced liver toxicity may include fatigue, abdominal pain, jaundice, and elevated liver enzymes in the blood [ 20 ]. Specifically, BNZ treatment results in elevations of AST, ALT, and ALP [ 38 ]. Our group has shown that a vaccine-linked chemotherapy strategy allows the reduction of BNZ dose, while still effectively reducing cardiac inflammation and fibrosis, and improving cardiac function [ 24 – 26 ].…”

Section: Discussionmentioning

confidence: 99%

The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection

Nguyen,

Poveda,

Pollet

et al. 2023

PLoS Negl Trop Dis

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Background Chagas disease, chronic infection with Trypanosoma cruzi, mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damage. We previously showed that combining low dose BNZ with a prototype therapeutic vaccine is a dose sparing strategy that effectively reduced T. cruzi induced cardiac damage. However, the impact of this treatment on liver health is unknown. Therefore, we evaluated several markers of liver health after treatment with low dose BNZ plus the vaccine therapy in comparison to a curative dose of BNZ. Methodology Female BALB/c mice were infected with a bioluminescent T. cruzi H1 clone for approximately 70 days, then randomly divided into groups of 15 mice each. Mice were treated with a 25mg/kg BNZ, 25μg Tc24-C4 protein/ 5μg E6020-SE (Vaccine), 25mg/kg BNZ followed by vaccine, or 100mg/kg BNZ (curative dose). At study endpoints we evaluated hepatomegaly, parasite burden by quantitative PCR, cellular infiltration by histology, and expression of B-cell translocation gene 2(BTG2) and Peroxisome proliferator-activated receptor alpha (PPARα) by RT-PCR. Levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were quantified from serum. Results Curative BNZ treatment significantly reduced hepatomegaly, liver parasite burdens, and the quantity of cellular infiltrate, but significantly elevated serum levels of ALT, AST, and LDH. Low BNZ plus vaccine did not significantly affect hepatomegaly, parasite burdens or the quantity of cellular infiltrate, but only elevated ALT and AST. Low dose BNZ significantly decreased expression of both BTG2 and PPARα, and curative BNZ reduced expression of BTG2 while low BNZ plus vaccine had no impact. Conclusions These data confirm toxicity associated with curative doses of BNZ and suggest that while dose sparing low BNZ plus vaccine treatment does not reduce parasite burdens, it better preserves liver health.

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“…Symptoms of BZN-induced liver toxicity may include fatigue, abdominal pain, jaundice, and elevated liver enzymes in the blood (20). Specifically, BNZ treatment results in elevations of AST, ALT, and ALP (38). Our group has shown that a vaccine-linked chemotherapy strategy allows the reduction of BNZ dose, while still effectively reducing cardiac inflammation and fibrosis, and improving cardiac function (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronicTrypanosoma cruziinfection

Jones

Nguyen

Poveda

et al. 2023

Preprint

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Background: Chagas disease, chronic infection with Trypanosoma cruzi, mainly manifests as cardiac disease. However, the liver is important for both controlling parasite burdens and metabolizing drugs. Notably, high doses of anti-parasitic drug benznidazole (BNZ) causes liver damage. We previously showed that combining low dose BNZ with a prototype therapeutic vaccine is a dose sparing strategy that effectively reduced T. cruzi induced cardiac damage. However, the impact of this treatment on liver health is unknown. Therefore, we evaluated several markers of liver health after treatment with low dose BNZ plus the vaccine therapy in comparison to a curative dose of BNZ. Methodology: Female BALB/c mice were infected with a bioluminescent T. cruzi H1 clone for approximately 70 days, then randomly divided into groups of 15 mice each. Mice were treated with a 25mg/kg BNZ, 25µg Tc24-C4 protein/ 5µg E6020-SE (Vaccine), 25mg/kg BNZ followed by vaccine, or 100mg/kg BNZ (curative dose). At study endpoints we evaluated hepatomegaly, parasite burden by quantitative PCR, cellular infiltration by histology, and expression of B-cell translocation gene 2(BTG2) and Peroxisome proliferator-activated receptor alpha (PPARα) by RT-PCR. Levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were quantified from serum. Results: Curative BNZ treatment significantly reduced hepatomegaly, liver parasite burdens, and the quantity of cellular infiltrate, but significantly elevated serum levels of ALT, AST, and LDH. Low BNZ plus vaccine did not significantly affect hepatomegaly, parasite burdens or the quantity of cellular infiltrate, but only elevated ALT and AST. Low dose BNZ significantly decreased expression of both BTG2 and PPARα, and curative BNZ reduced expression of BTG2 while low BNZ plus vaccine had no impact. Conclusions: These data confirm toxicity associated with curative doses of BNZ and suggest that the dose sparing low BNZ plus vaccine treatment better preserves liver health.

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Hepatic changes by benznidazole in a specific treatment for Chagas disease

Cited by 12 publications

References 24 publications

Frequency variation and dose modification of benznidazole administration for the treatment ofTrypanosoma cruziinfection in mice, dogs and non-human primates

Frequency variation and dose modification of benznidazole administration for the treatment ofTrypanosoma cruziinfection in mice, dogs and non-human primates

The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronic Trypanosoma cruzi infection

The impact of vaccine-linked chemotherapy on liver health in a mouse model of chronicTrypanosoma cruziinfection

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