Journal Article

Combined Treatment of Heterocyclic Analogues and Benznidazole upon Trypanosoma cruzi In Vivo

Oliveira, Gabriel Melo de, Stephens, Chad E., Soeiro, Maria de Nazaré Correia, Batista, Marcos Meuser, Rodrigues, Ana Carolina Mondaine, Boykin, David W., Batista, Denise da Gama Jaén, Britto, Constança Carvalho

2011

Overview

Chagas disease caused by Trypanosoma cruzi is an important cause of mortality and morbidity in Latin America but no vaccines or safe chemotherapeutic agents are available. Combined therapy is envisioned as an ideal approach since it may enhance efficacy by acting upon different cellular targets, may reduce toxicity and minimize the risk of drug resistance. Therefore, we investigated the activity of benznidazole (Bz) in combination with the diamidine prodrug DB289 and in combination with the arylimidamide DB766 upon T. cruzi infection in vivo. The oral treatment of T.cruzi-infected mice with DB289 and Benznidazole (Bz) alone reduced the number of circulating parasites compared with untreated mice by about 70% and 90%, respectively. However, the combination of these two compounds decreased the parasitemia by 99% and protected against animal mortality by 100%, but without providing a parasitological cure. When Bz (p.o) was combined with DB766 (via i.p. route), at least a 99.5% decrease in parasitemia levels was observed. DB766+Bz also provided 100% protection against mice mortality while Bz alone provided about 87% protection. This combined therapy also reduced the tissular lesions induced by T. cruzi infection: Bz alone reduced GPT and CK plasma levels by about 12% and 78% compared to untreated mice group, the combination of Bz with DB766 resulted in a reduction of GPT and CK plasma levels of 56% and 91%. Cure assessment through hemocultive and PCR approaches showed that Bz did not provide a parasitological cure, however, DB766 alone or associated with Bz cured ≥13% of surviving animals.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amidines - therapeutic use / Animals / Antifungal Agents - therapeutic use / Benzamidines - therapeutic use / Benznidazole / Biocompatibility / Biology / Chagas disease / Chagas Disease - drug therapy / Chagas Disease - mortality / Chagas Disease - parasitology / Chemotherapy / Combined treatment / Combined vaccines / Cytokines / Drug Combinations / Drug dosages / Drug resistance / Furans - therapeutic use / Health aspects / Heterocyclic compounds / Infection / Infections / Lesions / Male / Mice / Morbidity / Mortality / Nitroimidazoles - therapeutic use / Parasitemia / Parasitemia - blood / Parasitemia - drug therapy / Parasitemia - parasitology / Parasites / Plasma levels / Protozoa / Risk reduction / Rodents / Studies / Therapy / TNF inhibitors / Toxicity / Tropical diseases / Trypanocidal Agents - therapeutic use / Trypanosoma / Trypanosoma cruzi / Trypanosoma cruzi - drug effects / Tumor necrosis factor-TNF / Vaccines / Vector-borne diseases / Wildlife conservation