Phenothiazines and related compounds for Trypanosoma cruzi infection chemotherapy

RIVAROLA, W; LO PRESTI MS; BUSTAMENTE, J; PAGLINI-OLIVA, P

Florencia, Italia

Congreso; 7th European Congress of Chemotherapy and Infection; 2005

Federation of the European Societies for Chemotherapy and for Infection

The knowledge of the biology of Trypanosoma cruzi, causative agent of Chagas disease, and the sequencing of it’s genome, has provided the basis for identifying metabolic pathways as potential drug targets. Such targets must be characteristic of the parasite, but absent or modified in the host. The trypanothione reductase, enzyme of the trypanosomatides redox defence system, has been identified as one of these drug targets. This enzyme has shown to be irreversibly inhibited by the peroxidase/H2O2/phenothiazine complex. Phenothiazines and related compounds are tricyclic drugs used in psychiatric treatments as antidepressant, anxiolitic and anti-psychotic since they provoke dopamine receptors blockade. They also have anti-hemetic and anti-histaminic effects among many other biological activities. In the present work, we studied the effect of two tricyclic drugs, Clomipramine (used 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 in two doses: 60 min p.i. and 7 days p.i.) and Thioridazine (80 mg/kg/day for 3 days starting 1 h after the infection) upon the T. cruzi infection in mice, using two parasite strains (Tulahuen and SGO Z12); the drugs clinically used for the treatment of Chagas disease have high toxicity, many adverse secondary effects and frequently appear parasites resistant to them. In order to determine their effectiveness, we studied the parasite blood levels, survival, electrocardiography, histopathology and cardiac beta receptors density and affinity through their binding with trited dihidroalprenolol. Both drugs diminished blood parasite levels and improved the survival of the treated infected mice (p<0.05). The treatment with either drug was also effective in reducing the percentage of mice with electrocardiographic alterations in the chronic stage of the disease (p<0.05) and preventing the characteristic chronic myocardial structural damage. We also studied the cardiac beta receptors’ density and affinity as their alterations are characteristic of the infection: in the group infected with SGO Z12, treated mice had lower beta receptors’ affinity but higher density than the untreated ones (p<0.01), probably as a compensatory mechanism to maintain the cardiac function. In the Tulahuen infected group, the Clomipramine treated animals presented b receptor’s density and affinity not different from the non infected controls (p<0.01). These drugs, in addition to the trypanothine reductase inhibition, present other trypanocidal effects such as anti-calmodulin action, disruption of mitochondria and cell membrane disorganization. It thus seems clear that these drugs were effective against the acute phase of both T. cruzi strains infected mice and also prevented the acute phase evolving into the chronic disease and the associated cardiopathy, with no apparent adverse reactions. Survival of the treated infected mice was not different from the non-infected ones. These results demonstrate that Phenothiazines and related compounds are promising trypanocidal agents that could be effective for the treatment of Chagas´ disease, used alone or in combination with lower doses of the currently available drugs, probably diminishing their adverse secondary effects.