Trypanosoma cruzi: Chemotherapeutic effects of clomipramine in mice infected with an isolate obtained from an endemic area

Rivarola, Héctor Walter; Bustamante, Juan M.; Presti, María Silvina Lo; Fernández, Alicia Ruth; Enders, Jürgen; Gea, Susana; Fretes, Ricardo; Paglini-Oliva, Patrícia

doi:10.1016/j.exppara.2005.05.005

Cited by 27 publications

(26 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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%

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

mentioning

confidence: 99%

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

“…These results would show that clomipramine was not effective to prevent electrocardiographic alterations, but if one takes into account that most of the treated animals (n=37) were alive at this moment, whereas the untreated ones (n=7) were mostly dead, this difference could explain our findings. Treatment with this drug in the acute phase (Rivarola et al 2001(Rivarola et al , 2005 clearly prevented the electrical damage of the heart. Even though clomipramine and other antidepressant drugs are known to prolong the electrical heart conduction, provoking reversible changes in the QT segment (Coupland et al 1997), these side effects were not detected in our results because the electrocardiographic studies were performed 50 days after the end of the treatment and none of the animals died during clomipramine administration.…”

Section: Discussionmentioning

confidence: 94%

“…The incubation was concluded by adding 1 ml of cold incubation buffer to each tube and rapidly filtering the content under reduced pressure through Whatman GF/B filters. The filters were dried and transferred to vials with scintillation liquid (Aquasol Universal, NEN) for counting (Rivarola et al 2001;Bustamante et al 2003a,b;Rivarola et al 2005).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Chemotherapy of chronic indeterminate Chagas disease: a novel approach to treatment

et al. 2008

View full text Add to dashboard Cite

Treatment of Chagas disease is a controversial issue because the available drugs are highly toxic. Clomipramine is a tricyclic antidepressant drug that inhibits Trypanosoma cruzi's trypanothione reductase, provoking the death of the parasite and preventing the cardiac damage when used for the treatment of acutely infected mice. Here, we studied the effectiveness of clomipramine (5 mg/kg/day for one month) as chemotherapy for T. cruzi-infected mice in the chronic indeterminate stage of the infection. The animals were analyzed in the cardiac chronic phase. Survival of treated animals was 84% while for the untreated ones was 40%; most of the animals presented electrocardiographic abnormalities. Affinity and density of cardiac beta receptors from infected and treated mice were similar to those in the indeterminate phase, showing that clomipramine treatment stopped the increment of functional alterations provoked by the infection, while untreated mice presented affinity and density significantly diminished. Hearts from infected and untreated mice in the chronic stage presented mononuclear cells, necrosis and fiber dissolution while hearts from treated animals showed only isolated inflammatory infiltrates. Present results demonstrate that clomipramine used in the chronic indeterminate phase of the T. cruzi infection modified the natural evolution of the chagasic cardiopathy.

show abstract

“…These molecular targets must be parasite-specific, and their interaction with the trypanocidal drug should not produce any metabolic alteration in the mammalian host such as trypanothione reductase (TR) (Rojas et al 2007) and hypoxanthine-guanine ribosyltransferase (HGRT) (Gobbi 2007), both of which fulfill a vital function in the parasite. Clomipramine is a tricyclic drug used in psychiatric treatment which has been found to disable TR (Rivarola and Bustamante 2005). Allopurinol, in turn, disables the synthesis of guanylic acid and the adenylic pathway of HGRT (Marr and Docampo 1986).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

View full text Add to dashboard Cite

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.

show abstract

Trypanosoma cruzi: Chemotherapeutic effects of clomipramine in mice infected with an isolate obtained from an endemic area

Cited by 27 publications

References 29 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

Chemotherapy of chronic indeterminate Chagas disease: a novel approach to treatment

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

Contact Info

Product

Resources

About