Use of clomipramine as chemotherapy of the chronic phase of Chagas disease

Fauro, Romina; Presti, María Silvina Lo; Bazán, Carolina; Báez, Alejandra L.; Strauss, Mariana; Triquell, Fernanda; Cremonezzi, David; Negrete, Olga Sanchez; Camino-Willhuber, Gastón; Paglini-Oliva, Patrícia; Rivarola, Héctor Walter

doi:10.1017/s0031182013000103

Cited by 29 publications

(27 citation statements)

References 51 publications

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“…Particularly, BZ produces free radicals and/or electrophilic metabolites and induces oxidative stress in the parasite (17). On the other hand, CMP inhibits trypanothione reductase (22,40,43), an essential component of the antioxidant defenses of T. cruzi. As a consequence, it is plausible to think that these mechanisms would work together against the parasite.…”

Section: Discussionmentioning

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).…”

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confidence: 99%

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

García

Ponce

Sanmarco

et al. 2016

Antimicrob Agents Chemother

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

García

Ponce

Sanmarco

et al. 2016

Antimicrob Agents Chemother

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“…As with phenothiazines, these compounds have been previously reported to inhibit growth of T. cruzi [24], including a study showing activity of clomipramine in the mouse model of chronic T. cruzi infection [25]–[27]. The tricyclic antidepressants, similar to phenothiazines in structure, have also been shown to inhibit trypanothione reductase [28].…”

Section: Discussionmentioning

confidence: 99%

Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi

et al. 2014

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An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM), and an antifolate drug (pyrimethamine, EC50 of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.

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“…Parasite DNA loads in heart tissue have been determined by the SYBR Green method (Molina-Berrios et al, 2013) and by the TaqMan probe method (Fauro et al, 2013;Molina-Berríos et al, 2013).…”

Section: Quantification Of Parasite Dna In Tissue By Qpcrmentioning

confidence: 99%

Trypanosoma cruzi infectivity assessment in “in vitro” culture systems by automated cell counting

et al. 2015

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Use of clomipramine as chemotherapy of the chronic phase of Chagas disease

Cited by 29 publications

References 51 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

Synergy Testing of FDA-Approved Drugs Identifies Potent Drug Combinations against Trypanosoma cruzi

Trypanosoma cruzi infectivity assessment in “in vitro” culture systems by automated cell counting

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