Biological characterization of Trypanosoma cruzi strains

Martínez-Díaz, Rafael A.; Escario, José Antonio; Nogal-Ruiz, Juan José; Gómez‐Barrio, Alicia

doi:10.1590/s0074-02762001000100006

Cited by 46 publications

(39 citation statements)

References 26 publications

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“…The IC 50 of benznidazole for epimastigotes of the Y strain was determined to be 15 Ϯ 4 g ml Ϫ1 or 3 Ϯ 1 M and is about four to five times lower than that observed for parasites of the Colombiana strain (Fig. 1), as reported previously (24,33). Miltefosine had a higher level of cytotoxic activity against Y-strain epimastigotes than benznidazole, with the miltefosine IC 50 of 3.5 Ϯ 1 g ml Ϫ1 (8 Ϯ 1 M) being similar to data reported previously (21,36).…”

Section: Resultssupporting

confidence: 81%

Proinflammatory and Cytotoxic Effects of Hexadecylphosphocholine (Miltefosine) against Drug-Resistant Strains of Trypanosoma cruzi

Saraiva¹,

Gibaldi

Previato

et al. 2002

Antimicrob Agents Chemother

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The increased resistance of the protozoan parasite Trypanosoma cruzi to nitro derivatives is one of the major problems for the successful treatment of Chagas' disease. In the present study, we have tested the effects of 1-O-hexadecylphosphocholine (miltefosine) against strains of T. cruzi that are partially resistant (strain Y) and highly resistant (strain Colombiana) to the drugs in clinical use. As expected, epimastigotes of strain Colombiana showed higher levels of resistance to benznidazole than those of strain Y. However, the level of resistance to miltefosine was the same for both strains. This alkylphospholipid was also extremely toxic against intracellular amastigotes of both strains. This ether-lipid analogue induced in a dose-dependent manner the production of tumor necrosis factor alpha and nitric oxide (NO) radicals by infected and noninfected macrophages, suggesting that miltefosine may activate macrophages in vitro. Nevertheless, the cytotoxic effect of miltefosine against intracellular amastigotes was independent of the amount of NO produced by the infected macrophages since the same dose-response curves for miltefosine were observed when the NO production was blocked by the NO synthase inhibitor N G -monomethyl-L-arginine monoacetate. Preliminary in vivo studies with BALB/c mice infected with strain Y indicated that oral miltefosine promoted survival and reduced the parasitemia to levels comparable to those observed when benznidazole was used. Four months after treatment, no parasites were detected in the blood or spleen tissue sections maintained in culture. Together, these results support the hypothesis that miltefosine may be used for the treatment of Chagas' disease, including cases caused by resistant strains of T. cruzi.

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Section: Resultssupporting

confidence: 81%

Proinflammatory and Cytotoxic Effects of Hexadecylphosphocholine (Miltefosine) against Drug-Resistant Strains of Trypanosoma cruzi

Saraiva¹,

Gibaldi

Previato

et al. 2002

Antimicrob Agents Chemother

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“…The growth of CL B5 epimastigotes in LIT medium shows some differences in relation to Bolivia and GM strains (Martínez Díaz et al 2001) in the same experimental conditions. Although the peak of parasite concentration occurs at similar time for the three populations, for CL B5 it is slightly lower and the density at stationary phase is about 2 x 10 6 epimastigotes/ml, while with both strains the value of 20 x 10 6 epimastigotes/ml is maintained.…”

Section: Discussionmentioning

confidence: 87%

Biological characterization of a beta-galactosidase expressing clone of Trypanosoma cruzi CL strain

Le-Senne

Muelas-Serrano

Fernández-Portillo

et al. 2002

Mem. Inst. Oswaldo Cruz

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“…2C). This strain was previously described as partially benznidazole resistant and could provide a different setting for comparison of in vivo efficacy of the two drugs (27,28). Mice with established T. cruzi Y strain infection (35 to 55 days, depending on the duration of therapy) were treated with benznidazole at 100 mg/kg q.d.…”

Section: Resultsmentioning

confidence: 99%

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

Khare

Liu

Stinson

et al. 2015

Antimicrob Agents Chemother

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Two CYP51 inhibitors, posaconazole and the ravuconazole prodrug E1224, were recently tested in clinical trials for efficacy in indeterminate Chagas disease. The results from these studies show that both drugs cleared parasites from the blood of infected patients at the end of the treatment but that parasitemia rebounded over the following months. In the current study, we sought to identify a dosing regimen of posaconazole that could permanently clear Trypanosoma cruzi from mice with experimental Chagas disease. Infected mice were treated with posaconazole or benznidazole, an established Chagas disease drug, and parasitological cure was defined as an absence of parasitemia recrudescence after immunosuppression. Twenty-day therapy with benznidazole (10 to 100 mg/kg of body weight/day) resulted in a dose-dependent increase in antiparasitic activity, and the 100-mg/kg regimen effected parasitological cure in all treated mice. In contrast, all mice remained infected after a 25-day treatment with posaconazole at all tested doses (10 to 100 mg/kg/day). Further extension of posaconazole therapy to 40 days resulted in only a marginal improvement of treatment outcome. We also observed similar differences in antiparasitic activity between benznidazole and posaconazole in acute T. cruzi heart infections. While benznidazole induced rapid, dose-dependent reductions in heart parasite burdens, the antiparasitic activity of posaconazole plateaued at low doses (3 to 10 mg/kg/day) despite increasing drug exposure in plasma. These observations are in good agreement with the outcomes of recent phase 2 trials with posaconazole and suggest that the efficacy models combined with the pharmacokinetic analysis employed here will be useful in predicting clinical outcomes of new drug candidates.

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Biological characterization of Trypanosoma cruzi strains

Cited by 46 publications

References 26 publications

Proinflammatory and Cytotoxic Effects of Hexadecylphosphocholine (Miltefosine) against Drug-Resistant Strains of Trypanosoma cruzi

Proinflammatory and Cytotoxic Effects of Hexadecylphosphocholine (Miltefosine) against Drug-Resistant Strains of Trypanosoma cruzi

Biological characterization of a beta-galactosidase expressing clone of Trypanosoma cruzi CL strain

Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease

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