Thioridazine: Treatment of Experimental Acute and Chronic Trypanosoma cruzi Infection with an Isolate from an Endemic Area

LO PRESTI MS; BUSTAMANTE JM; RIVAROLA HW; FRETES R; PAGLINI PA.

Chigago, EEUU

Conferencia; 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2007

American Society of Microbiology

Background: Novel antiparasitic drugs for the treatment of Chagas disease, developed on the basis of the biochemistry of Trypanosoma cruzi, include inhibitors of trypanotione reductase (TR). Thioridazine (THI) is a phenothiazine with a potent TR inhibition effect that prevented the cardiopathy in T. cruzi (Tulahuen strain) infected mice. Since not all parasite strains show the same response to treatment, we studied the effectiveness of THI in mice inoculated with the SGO Z12 isolate (obtained from an endemic area of Argentina) in the acute or the chronic phases of the infection. Methods: Mice infected with 50 trypomastigote forms (SGO Z12 isolate) were treated orally with THI 80 mg/kg/day, for 3 days starting 1 h after infection (n=42) and studied 135 days post infection (dpi) or with THI 80 mg/kg/day for 12 days, 180 dpi (n=20) and studied 350 dpi. Infected and untreated (n=62) and uninfected and treated with isotonic saline solution mice (n=32) were also studied. Parasitemia, survival, electrocardiography (ECG), cardiac histopathology and cardiac b receptors density and affinity, were studied. Results: THI in the acute phase reduced the parasitemia, ECG and histological alterations and significantly improved survival (P<0.01). Treated mice had lower receptor affinity and higher density as a compensatory mechanism. THI in the chronic phase significantly improved survival (treated: 88 %; untreated: 40 %), reduced ECG and cardiac â receptors alterations (P<0.01). Few isolated areas of fibrosis were found whereas untreated mice showed necrosis and fiber fragmentation. Conclusion: Treatment in the acute phase modified the course of the infection and prevented the cardiopathy. These results also reinforce the importance of treatment in the chronic phase  to decrease, retard or stop the evolution to chagasic myocardiopathy. THI should be considered as a potential agent for the treatment of Chagas disease, with no aparent toxic effects at the dose and treatment schedule used.