Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi
            <i>In Vitro</i>
            and
            <i>In Vivo</i>

Pandey, Ramendra Pati; Nascimento, Marilda Savóia; Franco, Caio Haddad; Bortoluci, Karina Ramalho; Silva, Marcelo Nunes; Zingales, Bianca; Gibaldi, Daniel; Barrios, Leda Castaño; Lannes‐Vieira, Joseli; Cariste, Leonardo Moro; Vasconcelos, José Ronnie; Moraes, Carolina Borsoi; Freitas‐Junior, Lúcio H.; Kalil, Jorge; Alcântara, Laura Maria; Cunha‐Neto, Edécio

doi:10.1128/aac.00284-22

Cited by 10 publications

(7 citation statements)

References 62 publications

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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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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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“…42 In addition, factors such as age, geographic distribution, the immune background of the host and the natural resistance of some strains of T. cruzi to the drug can affect the effectiveness of the treatment. [43][44][45] In this context, we sought to evaluate the cytokine profile in observed in a prospective cohort study where a significant reduction in parasitemia, lower prevalence of markers of severe cardiomyopathy and lower mortality after 2 years of follow-up of patients with chronic Chagas disease who received at least one cycle of BZ treatment. 53 BZ is a relevant drug in immunomodulatory changes, although it has many negative points, such as its use in chronic patients with cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of the available drugs BZ and Nifurtimox is low in the chronic phase of Chagas disease, the phase in which most patients are diagnosed, and there are frequent side effects 42 . In addition, factors such as age, geographic distribution, the immune background of the host and the natural resistance of some strains of T. cruzi to the drug can affect the effectiveness of the treatment 43–45 …”

Section: Discussionmentioning

confidence: 99%

TNF blockers alone and associated with Benznidazole impact in vitro cytokine dynamics in chronic Chagas disease

Torres,

dos Santos Oliveira,

da Silva Barros

et al. 2024

Parasite Immunology

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Studies involving the immune response in Chagas disease suggest an imbalance in the immune response of symptomatic patients, with an inflammatory profile dominating in Chagas heart disease, mainly by tumour necrosis factor (TNF). TNF is considered a key cytokine in immunopathology in chronic carriers in several processes during the immune response. Our work aimed to evaluate regulatory (interleukin [IL]‐4 and IL‐10) and inflammatory (TNF, interferon‐gamma [IFN‐γ], IL‐2 and IL‐6) cytokines in peripheral blood mononuclear cells culture supernatants. of affected patients with undetermined clinical forms—IND (n = 13) mild heart form—CARD1 (n = 13) and severe cardiac form—CARD2 (n = 16), treated in vitro with two TNF blockers, Adalimumab (ADA) and Etanercept (ETA) alone or in association with Benznidazole (BZ). The results indicate that ADA was more competent in blocking TNF (compared to ETA) in all groups but with much lower levels in the CARD2 group. ETA statistically decreased TNF levels only in the CARD2 group. IFN‐γ increased in the CARD2 group after treatment with ETA relative to ADA. IL‐4 had its levels decreased when treated by both drugs. IL‐2 was detected in cells from CARD2 carriers compared to the NEG group after treatment with both drugs. The association with BZ decreased levels of IL‐2/TNF and increased IL‐4. These data reinforce the participation of TNF in severe Chagas heart disease and bring perspectives on using these blockers in the immunological treatment of Chagas disease since the use of BZ is extremely limited in these patients.

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“…Previous studies have shown that chloroquine, hydroxychloroquine [23], and primaquine [24] have activity against different species of Leishmania. Moreover, chloroquine also showed improved activity when used together with benznidazole, the standard treatment against Trypanosoma cruzi [25]. On the other hand, insecticides used for vector elimination have also been tested against some parasites, sometimes obtaining activity against kinetoplastids [26], although this is a complex field due to parasite adaptations.…”

Section: Discussionmentioning

confidence: 99%

Global Health Priority Box: Discovering Flucofuron as a Promising Antikinetoplastid Compound

Bethencourt-Estrella,

López-Arencibia,

Lorenzo-Morales

et al. 2024

Pharmaceuticals

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Leishmaniasis, produced by Leishmania spp., and Chagas disease, produced by Trypanosoma cruzi, affect millions of people around the world. The treatments for these pathologies are not entirely effective and produce some side effects. For these reasons, it is necessary to develop new therapies that are more active and less toxic for patients. Some initiatives, such as the one carried out by the Medicines for Malaria Venture, allow for the screening of a large number of compounds of different origins to find alternatives to the lack of trypanocide treatments. In this work, 240 compounds were tested from the Global Health Priority Box (80 compounds with confirmed activity against drug-resistant malaria, 80 compounds for screening against neglected and zoonotic diseases and diseases at risk of drug resistance, and 80 compounds with activity against various vector species) against Trypanosoma cruzi and Leishmania amazonensis. Flucofuron, a compound with activity against vectors and with previous activity reported against Staphylococcus spp. and Schistosoma spp., demonstrates activity against L. amazonensis and T. cruzi and produces programmed cell death in the parasites. Flucofuron seems to be a good candidate for continuing study and proving its use as a trypanocidal agent.

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Drug Repurposing in Chagas Disease: Chloroquine Potentiates Benznidazole Activity against Trypanosoma cruzi In Vitro and In Vivo

Cited by 10 publications

References 62 publications

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

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

TNF blockers alone and associated with Benznidazole impact in vitro cytokine dynamics in chronic Chagas disease

Global Health Priority Box: Discovering Flucofuron as a Promising Antikinetoplastid Compound

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