Clomipramine and benznidazole association for the treatment of acute experimental Trypanosoma cruzi infection

Strauss, Mariana; Presti, María Silvina Lo; Bazán, Paula Carolina; Báez, Alejandra L.; Fauro, Romina; Esteves, Blanca H.; Negrete, Olga Sanchez; Cremonezzi, David; Paglini-Oliva, Patrícia; Rivarola, Héctor Walter

doi:10.1016/j.parint.2013.02.004

Cited by 30 publications

(28 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This drug combination overrides parasitemia and induces a significant diminution of relative spleen weights in comparison with infected control mice (P Ͻ 0.001). Our results are in agreement with a previous work in which BZ at 50 mg/kg/day administered by the oral route was combined with the intraperitoneal administration of CMP at 5 mg/kg/day (23). It is important to highlight that the intraperitoneal route is rarely used for systemic drug administration in human medicine (44,45).…”

Section: Discussionsupporting

confidence: 92%

“…*, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001; ns, no significant difference. tions (16), while the presence of CMP seemed not to induce additional apparent injuries (23).…”

Section: Discussionmentioning

confidence: 85%

“…All groups showed 100% survival under the evaluated conditions. It was observed that the therapeutic dose of BZ currently used in the Chagas mouse model (100 mg/kg/day) (5,23) and BZ at 50 mg/kg/day were able to override the parasitemia. As was expected, BZ at 25 mg/kg/day and 12.5 mg/kg/day only decreased the parasitemia levels (P Ͻ 0.001) relative to those of the INT group.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, clomipramine (CMP), a tricyclic antidepressant, inhibits trypanothione reductase activity and has evidenced antitrypanocidal activity when used alone (22,49) or in combination with BZ (23). Furthermore, considering the possible existence of resistant parasite strains and more than one strain in the same patient, combined treatment with two drugs bearing different mechanisms of action might be a strategy to improve the pharmacotherapy of Chagas disease (14,23,24).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

García

Ponce

Sanmarco

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

bChagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.

show abstract

Section: Discussionsupporting

confidence: 92%

“…*, P Ͻ 0.05; **, P Ͻ 0.01; ***, P Ͻ 0.001; ns, no significant difference. tions (16), while the presence of CMP seemed not to induce additional apparent injuries (23).…”

Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

García

Ponce

Sanmarco

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Despite the existence of pharmacokinetic studies of BNZ in some animal species, the preclinical pharmacokinetics of BNZ is still little studied and with poor results. Several pre-clinical studies are being conducted to evaluate the antichagasic activity of the association of BNZ with other drugs (Diniz et al, 2013;Strauss et al, 2013) et al, 2011) should use pharmacokinetic data for planning pharmacodynamic and toxicity assays.…”

Section: Methods Validationmentioning

confidence: 99%

Rapid and sensitive ultra‐high‐pressure liquid chromatography method for quantification of antichagasic benznidazole in plasma: application in a preclinical pharmacokinetic study

Davanço

Campos

Peccinini

2014

Biomedical Chromatography

View full text Add to dashboard Cite

Benznidazole (BNZ) and nifurtimox are the only drugs available for treating Chagas disease. In this work, we validated a bioanalytical method for the quantification of BNZ in plasma aimed at improving sensitivity and time of analysis compared with the assays already published. Furthermore, we demonstrated the application of the method in a preclinical pharmacokinetic study after administration of a single oral dose of BNZ in Wistar rats. A Waters® Acquity UHPLC system equipped with a UV-vis detector was employed. The method was established using an Acquity® UHPLC HSS SB C18 protected by an Acquity® UHPLC HSS SB C18 VanGuard guard column and detection at 324 nm. The mobile phase consisted of ultrapure water-acetonitrile (65:35), and elution was isocratic. The mobile phase flow rate was 0.55 mL/min, the volume of injection was 1 μL, and the run time was just 2 min. The samples were kept at 25°C until injection and the column at 45°C for the chromatographic separation. The sample preparation was performed by a rapid protein precipitation with acetonitrile. The linear concentration range was 0.15-20 µg/mL. The pharmacokinetic parameters of BNZ in rats were determined and the method was considered sensitive, fast and suitable for application in pharmacokinetic studies.

show abstract

Trypanothione reductase inhibitors: Overview of the action of thioridazine in different stages of Chagas disease

et al. 2015

Self Cite

View full text Add to dashboard Cite

Clomipramine and benznidazole association for the treatment of acute experimental Trypanosoma cruzi infection

Cited by 30 publications

References 34 publications

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease

Rapid and sensitive ultra‐high‐pressure liquid chromatography method for quantification of antichagasic benznidazole in plasma: application in a preclinical pharmacokinetic study

Trypanothione reductase inhibitors: Overview of the action of thioridazine in different stages of Chagas disease

Contact Info

Product

Resources

About