Association of clomipramine and allopurinol for the treatment of the experimental infection with Trypanosoma cruzi

Abstract

We have previously shown that clomipramine and allopurinol used separately are effective in preventing chronic chagasic cardiomyopathy. The aim of the present study was to evaluate the effect of the association of clomipramine (Clo--5 mg/kg/day/90 days) and allopurinol (Allo--5, 10, or 15 mg/kg/day/90 days) for the treatment of experimental Chagas disease in the acute stage. Treatment effectiveness was evaluated through parasitemia, survival, electrocardiography, serology, and cardiac histopathology. Groups treated showed no electrocardiographic abnormalities, in contrast to those untreated which presented 25% of mice with conduction alterations. The myocardium of treated mice (Clo, Allo10+Clo, and Allo15+Clo) presented no structural alterations. Cardiac b-receptor affinity was preserved in mice treated with Clo or Clo+Allo at the different doses; receptor density of the Clo and Allo15+Clo groups did not differ from the non-infected group. Anti-cruzipain antibody levels were similar in treated and untreated groups. Survival was significantly increased in the treated groups (p < 0.05), with Clo and all the Clo+Allo groups presenting the highest rates. These results show that the association of clomipramine + allopurinol is effective for Chagas disease treatment and has the same effect as clomipramine alone.

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

“…For this reason, in the last 2 decades, new approaches focusing on parasite-specific targets to address this illness have been studied, and different strategies with the overall aim of finding a cure for Chagas disease are under investigation. In particular, we focused on trypanothione reductase, a specific enzyme of T. cruzi that performs vital functions in the parasite, and on CMP, which presents inhibitory effects on trypanothione reductase activity (40).…”

“…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.…”

Evaluation of benznidazole treatment combined with nifurtimox, posaconazole or AmBisome® in mice infected with Trypanosoma cruzi strains

“…This approach might improve the efficacy of treatment (by generating additive or synergistic effects on different pharmacological targets) and decrease the likelihood of drug resistance and toxic effects (by reducing the drug dosages or treatment durations used). Several associations of two drugs inducing limited improvements in mice [15][16][17][18][19][20] or in patients [21] have been tested. However, as far as we know, no experimental studies or clinical trials combining the already patented drugs available on the market (BZL, NFX, POS and AMB) have been reported.…”

Elucidating the impact of low doses of nano-formulated benznidazole in acute experimental Chagas disease

“…Even though it is widely prescribed, there are major concerns related with the frequency of serious side effects, including allergic dermatitis, gastrointestinal intolerance, anorexia, weight loss and sleeping disorders [ 6 ]. Several authors have reported different treatments in experimental murine model using lower doses of BNZ alone or combined with other drugs, to improve treatment efficacy and decrease adverse side effects [ 7 , 8 , 9 ]. Despite the fact that these reports have shown certain benefits in terms of survival rate and lower parasitemia, there is an urgent need to develop novel therapeutic alternatives using low doses of BNZ for further successful clinical translation.…”