Chagas’ disease treatment with Clomipramine and Thioridazine upon an infection produced by an isolate obtained from a chronic patient

RIVAROLA, W; LO PRESTI, S; BUSTAMANTE, JM; FERNANDEZ, AR; ENDERS, J; FRETES, R; PAGLINI, P

Cooper Mountain, Colorado, USA.

Simposio; Symposia on Infectious Diseases. Drugs Against Protozoan Parasites: Target Selection, Structural Biology and Medicinal Chemistry. Keystone Symposia.; 2005

Previous works in our laboratory have demonstrated that some tricyclic drugs such as clomipramine (Clo) and thioridazine (Thi) are lethal for trypomastigotes and epimastigotes forms of Trypanosoma cruzi Tulahuen strain probably through their anti-trypanothione reductase and anti-calmodulin effects. This drugs prevented the evolution to the chronic phase of the disease in mice infected with this parasite strain. As not all T. cruzi strains show equal sensibility to treatment, in the present work we studied if these drugs (Thi 80 mg/Kg/day for 3 days starting 1 h after the infection; Clo in two treatment schedules: 5 mg/kg/day for 30 days, the first dose 60 min post-infection (p.i.) and 40 mg/kg/day 60 min p.i. and 7 days p.i.) were effective upon an infection produced by an isolate obtained from a chronic patient. The treatment with either drug was effective in reducing the parasite blood levels, the electrocardiographic alterations and preventing the characteristic myocardial structural damage, significantly improving the survival of the treated animals (60 – 70 % of the Clo treated mice survived 135 days p.i. while only 30 % of the non treated were alive at this time; 50 % of the Thi treated survived while 80 % of the non treated died). We also studied the cardiac β receptors’ density and affinity as their alterations are characteristic of the infection: treated mice had lower β receptors’ affinity but higher density than the untreated ones (p<0.01), probably as a compensatory mechanism to maintain the cardiac function. The anti-cruzipain titres remained high in all the treated groups, but 135 days post infection would be not enough time to reverse IgG titres, as has been proposed by several authors. The present results demonstrate that Clo and Thi, currently used as neuroleptics, are effective against different T. cruzi strains becoming promising trypanocidal agents for the treatment of Chagas´ disease, without showing any apparent secondary effect.