Pentamidine antagonizes the benznidazole's effect in vitro, and lacks of synergy in vivo: Implications about the polyamine transport as an anti-Trypanosoma cruzi target
Verónica SeguelLorena CastroChantal ReigadaLeonel A. CortesMaría V. DíazMariana R. MirandaClaudio A. PereiraMichel LapierCarolina Campos‐EstradaAntonio MorelloUlrike KemmerlingJuan Diego MayaRodrigo López‐Muñoz
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Keywords:
Benznidazole
Pentamidine
Amastigote
Chagas Disease
Nifurtimox
Kinetoplastida
Trypanocidal agent
Polyamine
The treatment of Chagas disease (CD), a neglected parasitic condition caused by Trypanosoma cruzi , is still based on only two drugs, nifurtimox ( Nif ) and benznidazole ( Bz ), both of which have limited efficacy in the late chronic phase and induce severe side effects. This scenario justifies the continuous search for alternative drugs, and in this context, the natural naphthoquinone β-lapachone ( β-Lap ) and its derivatives have demonstrated important trypanocidal activities. Unfortunately, the decrease in trypanocidal activity in the blood, high toxicity to mammalian cells and low water solubility of β-Lap limit its systemic administration and, consequently, clinical applications. For this reason, carriers as drug delivery systems can strategically maximize the therapeutic effects of this drug, overcoming the above mentioned restrictions. Accordingly, the aim of this study is to investigate the in vitro anti- T . cruzi effects of β-Lap encapsulated in2-hydroxypropyl-β-cyclodextrin ( 2HP-β-CD ) and its potential toxicity to mammalian cells.
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ABSTRACT American trypanosomiasis, or Chagas' disease, is caused by Trypanosoma cruzi and affects around 15 million people throughout the American continent. The available treatment is based on two nitroheterocyclic drugs, nifurtimox and benznidazole, both only partially effective and toxic. In this context, new drugs must be found. In our previous work, the tetrahydro-β-carboline compound N -butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide, named C4, showed a potent in vitro trypanocidal effect. The goal of this study was to evaluate the in vitro and in vivo trypanocidal effects of the compound C4 associated with other drugs (benznidazole, ketoconazole, and amphotericin B). For this, we used the checkerboard technique to analyze the effect of combinations of C4 reference drugs. C4 was assayed in a murine model alone as well as in association with benznidazole. We also evaluated the parasitemia, mortality, weight, and presence of amastigote nests in cardiac tissue. A synergic effect of C4 plus benznidazole against epimastigote and trypomastigote forms was observed in vitro , and in the murine model, we observed a substantial reduction in parasitemia levels and lowered mortality rates. These findings encourage supplementary investigations of carboline compounds as potential new trypanocidal drugs.
Benznidazole
Trypanocidal agent
Nifurtimox
Chagas Disease
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Benznidazole
Chagas Disease
Nifurtimox
Trypanocidal agent
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The trypanocidal activity of N-allyl (NAOx) and N-propyl (NPOx) oxamates and that of the ethyl esters ofN-allyl (Et-NAOx) and N-propyl (Et-NPOx) oxamates were tested on cultured epimastigotes (in vitro) and murine trypanosomiasis (in vivo) using five different T. cruzi strains. NAOx and NPOx did not penetrate intact epimastigotes and therefore we were not able to detect any trypanocidal effect with these oxamates. Whereas the ethyl esters (Et-NAOx and Et-NPOx), acting as prodrugs, exhibited in vitro and in vivo trypanocidal activity on the five tested T. cruzi strains. On the contrary, when Nifurtimox and Benznidazole used as reference drugs were tested, we found that only three of the five tested T cruzi strains were affected, whereas the other two strains, Miguz and Compostela, were resistant to the in vitro and in vivo trypanocidal activity of these compounds.
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Nifurtimox
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Chagas Disease
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Benznidazole
Nifurtimox
Trypanocidal agent
Chagas Disease
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Amastigote
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Advocacy for better drugs and access to treatment has boosted the interest in drug discovery and development for Chagas disease, a chronic infection caused by the genetically heterogeneous parasite, Trypanosoma cruzi. In this work new in vitro assays were used to gain a better understanding of the antitrypanosomal properties of the most advanced antichagasic lead and clinical compounds, the nitroheterocyclics benznidazole, nifurtimox and fexinidazole sulfone, the oxaborole AN4169 and four ergosterol biosynthesis inhibitors – posaconazole, ravuconazole, EPL-BS967 and EPL-BS1246. Two types of assays were developed: one for evaluation of potency and efficacy in dose-response against a panel of T. cruzi stocks representing all current discrete typing units (DTUs) and a time-kill assay. Although less potent, the nitroheterocyclics and the oxaborole showed broad efficacy against all T. cruzi tested and were rapidly trypanocidal, whilst ergosterol biosynthesis inhibitors showed variable activity that was both compound- and strain-specific and were unable to eradicate intracellular infection even after 7 days of continuous compound exposure at most efficacious concentrations. These findings contest previous reports of variable responses to nitroderivatives among different T. cruzi strains and further challenge the introduction of ergosterol biosynthesis inhibitors as new single chemotherapeutic agents for the treatment of Chagas disease.
Benznidazole
Nifurtimox
Posaconazole
Chagas Disease
Trypanocidal agent
Ergosterol
Antiparasitic agent
Drug Development
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The trypanocidal activity of N-isopropyl oxamate (NIPOx) and the ethyl ester of N-isopropyl oxamate (Et-NIPOx) were tested on cultured epimastigotes (in vitro) and on murine trypanosomiasis (in vivo) using five different T. cruzi strains. When benznidazole and nifurtimox, used for comparison, were tested we found that only three of these T. cruzi strains were affected, whereas the other two strains, Miguz and Compostela, were resistant to the in vitro and the in vivo trypanocidal activity of these substances. In addition, when NIPOx was tested on cultured epimastigotes and on mice parasitaemia, trypanocidal activity was not obtained on either of these T. cruzi strains. Our experiments strongly suggest that NIPOx does not penetrate intact epimastigotes due to the polarity of its carboxylate whereas Et-NIPOx, acting as a prodrug, exhibited in vitro and in vivo trypanocidal activity in the five tested T. cruzi strains.
Benznidazole
Nifurtimox
Chagas Disease
Trypanocidal agent
Isopropyl
Infectivity
Kinetoplastida
Antiparasitic
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