Benznidazole

Benznidazole, a nitroimidazole derivative, has a mode of action that seems to involve covalent modification of macromolecules by nitroreduction intermediates. 

The drugs used for T. cruzi include nifurtimox (Lampit) and benznidazole (Rochagan). Oral nifurtimox is available from the CDC, while benznidazole is only available in Brazil. The adult dose of nifurtimox is 8 to 10 mg/kg per day in divided doses for 120 days. Since children seem to tolerate the dose better than adults, the pediatric dose of nifurtimox in children 1 to 10 years old is 15 to 20 mg/kg per day, and the dose for children 11 to 16 years old is 12.5 to 15 mg/kg per day in divided doses. Symptomatic treatment for heart failure associated with Chagas disease should be initiated. The gastrointestinal complications may require surgical revisions and reconstruction. 

The in vitro trypanocidal and antitumor activities of lfr(cot)L], cot = cyclotetraene, derivatives of dithiocarbamates and xanthates, have been investigated.700 The Ir complexes were characterized by IR spectroscopy, and MO calculations (Hiickel) were performed on the ligands. Similar studies were performed on [Ir(nbr)L], nbr = norbornadiene, L = derivatives of alquil and aryl xanthates 701 and also on [Ir2(cod)2L]X2, where L = 2-hydroxystilbamidine, X = C1, N03, C104, BPh4, and [Ir(cod)L2 ]X, where L = benznidazole, R0-2516, nifurtimox, niridazole. The complex [Ir2(cod)2(2-hydroxystilbami-dine)](BPh4)2 showed the highest activity, as studied by optical microscopy of rats kidneys. 

Masana M, de Toranzo EG, Castro JA. Reductive metabolism and activation of benznidazole. Biochem Pharmacol 1984 33(7) 1041-1045. 

Benznidazole is an orally administered nitroimidazole that appears to have efficacy similar to that of nifurtimox in the treatment of acute Chagas disease. Availability of the drug is currently limited. Important toxicities include peripheral neuropathy, rash, gastrointestinal symptoms, and myelosuppression. 

Andrade AL et al Short report Benznidazole efficacy among Trypanosoma cruzi-infected adolescents after a six-year follow-up. Am J Trop Med Hyg 2004 71 594. [PMID 15569790]... 

Viotti R et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment A nonrandomized trial. Ann Intern Med 2006 144 724. [PMID 16702588]... 

Chaga s disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America, and represents a very serious public health problem in several countries. At present, the only available therapeutic agent for Chaga s disease is benznidazole. This nitroheterocyclic compound is not... 

Radiosensitizing effect in hypoxic cells [89] toxicity to hypoxic cells [102, 112, 115, 116] DNA damage [112], antitrichomonal activity [137], structure-activity [115, 116] inhibition of T. cruzi growth at concentrations that do not stimulate 0 and H202 production (reduced metabolites of benznidazole are involved through covalent binding to macromolecules in its trypanocidal and toxic effects) [133]... 

Benznidazole is a nitroimidazole that may occasionally cause peripheral neuritis but is generally weU tolerated, including by infants. 

The adverse effects of benznidazole can be classified into three groups (2,3) ... 

In a double-blind, randomized, clinical trial, benznidazole 5 mg/kg/day for 60 days was compared with placebo in children in the indeterminate phase of infection by Trypanosoma cruzi (1). In general, treatment was well tolerated. The treated children had a significant reduction in mean titers of antibodies against T. cruzi measured by indirect hemagglutination, indirect immunofluorescence, and ELISA. At 4-year follow-up, 62% of the benznidazole-treated children and no placebo-treated chUd were seronegative for T. cruzi. Xenodiagnosis after 48 months was positive in 4.7% of the benznidazole-treated children and in 51% of the placebo-treated children. 

Like metronidazole, benznidazole is mutagenic. In tests for chromosomal aberrations and induction of micronuclei in cultures of peripheral lymphocytes from children with Chagas disease, there were increases in micro-nucleated interphase lymphocytes and of chromosomal aberrations after treatment with benznidazole (4). 

Like metronidazole, benznidazole has a disulfiram-like effect if alcohol is taken (5). 

Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas disease. Am J Trop Med Hyg 1998 59(4) 526-9. 

Cancado JR. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop Sao Paulo 2002 44(l) 29-37. 

Castro JA, Diaz de Toranzo EG. Toxic effects of nifurtimox and benznidazole, two drugs used against American trypanosomiasis (Chagas disease). Biomed Environ Sci 1988 l(l) 19-33. 

Benznidazole Nucleic acid synthesis Activation in the parasite Trypanosoma spp. 

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