Nifurtimox induced ultrastructural and biochemical alterations in rat heart. Their potential relevance in the treatment of chaga?s disease.

BARTEL LC; MONTALTO DE MECCA M; R. DE CASTRO, C; FANELLI SL; DÍAZ EG ; CASTRO JA

Cavtat/Dubrovnik

Congreso; EUROTOX 2006/.CTDC Congress. 43th Congress of European Societies of Toxicology. 6th Congress of Toxicology in Developing Countries.; 2006

European Societies of Toxicology

Chagas? disease is an endemic parasitic disease in some areas of Latin America. About 16-18 million people suffer this sickness and more than 100 million are living at risk of getting the infection. Life threatening myocarditis can occur during the acute phase of the disease. About 20-25 % of the surviving patients of the acute phase develop the chronic phase, which is characterized by potential lethal cardiopathy. There are available two drugs for the ethiological treatment of the disease, Nifurtimox (Nfx) and Benznidazol (Bz). They are being used in the acute phase and more recently they were used in the asimptomatic intermediate phase. This is developed after the acute and before the chronic phase and when the deleterious effects of the disease in heart could be already in course. Both nitroheterocyclic drugs have serious toxic side effects which compromised their use. The mechanism of toxicity is associated with their nitroreduction and the generation of reactive metabolites. However, their potential effects on cardiac function are yet not known. In this study we describe initial experiments to test the acute effects on rat heart. Male Sprague Dawley rats (18 weeks, 280-320 g bw) were treated intragastrically with Nfx at a dose of 100 mg/kg bw suspended in 1% carboxymethylcellulose. Control rats received the same amount of the vehicle. We observed that the administered drug reached the heart tissue at 1, 3 and 6 h after treatment. Studies on Nfx nitroreductase activity showed that the microsomal fraction had the ability to nitroreduce Nfx. With respect to the biochemical effects due to protein oxidation processes, we observed an increase in protein carbonyl content of treated rats at 1 and 3 h and a protein sulfhydryl decreasing content was observable only at 3 h after treatment, being undetectable at 1 and 6 h. No increases in the t-buthyl hydroperoxide induced chemiluminiscence were observed at 1, 3, 6 and 24 h after Nfx administration. However, at 24 h after treatment ultrastructural alterations were observable in the heart. They consisted in a marked vacuolization of the cytoplasm, the separation and loss of myofibrils and mitochondrial swelling too. Furthermore, most cells showed clumping of the chromatin adjacent to the nuclear membrane. Results suggest that Nfx administration might aggravate pre-existing adverse cardiac conditions. This work was supported by SECyT and by the University of San Martín. Argentina.