Current and developing therapeutic agents in the treatment of Chagas disease

Abstract

Chagas disease must be treated in all its stages: acute, indeterminate, chronic, and initial and middle determinant chronic, due to the fact that DNA of the parasite can be demonstrated by PCR in chronic cases, where optical microscopy does not detect parasites. Nifurtimox (NF) and benznidazole (BNZ) are the drugs accepted to treat humans based upon ethical considerations and efficiency. However, both the drugs produce secondary effects in 30% of the cases, and the treatment must be given for at least 30-60 days. Other useful drugs are itraconazole and posaconazole. The latter may be the drug to treat Chagas disease in the future when all the investigations related to it are finished. At present, there is no criterion of cure for chronic cases since in the majority, the serology remains positive, although it may decrease. In acute cases, 70% cure with NF and 75% with BNZ is achieved. In congenital cases, 100% cure is obtained if the treatment is performed during the first year of life. In chronic acquired cases, 20% cure and 50% improvement of the electrocardiographic changes are obtained with itraconazole.

Keywords: Chagas disease; allopurinol; benznidazole; itraconazole; nifurtimox; posaconazole; treatment.

Figure 1

Biosynthesis of glutathione and trypanothione in T. cruzi: Glutathione is synthesized by the consecutive action of γ-glutamylcysteine synthetase and glutathione synthetase in an ATP-dependent reaction. In T. cruzi, two molecules of glutathione are conjugated with spermidine to synthesize trypanothione (N¹, N⁸-bisglutathionylspermidine, T(SH)₂). The host is unable to synthesize T(SH)₂. γ-Glutamylcysteine synthetase is the step-limiting enzyme in this process and can be inhibited by BSO.

Figure 2

Chemical structure of triazole derivatives, inhibitors of T. cruzi sterol C14α sterol demethylase.

Figure 3

Role of glutathione and trypanothione in the action and metabolism of the anti-Chagasic drugs nifurtimox and benznidazole. The nitro group of both anti-Chagasic drugs is reduced to free radicals or electrophilic metabolites by T. cruzi cytochrome P450-related nitroreductases. The nifurtimox-derived free radicals may undergo redox cycling with oxygen, and H₂O₂ is produced by the further action of superoxide dismutase (SOD). The produced oxygen-derived free radicals and electrophilic metabolites bind to intracellular macromolecules, damaging them. In the parasite, trypanothione (T(SH) ₂) and glutathione (GSH) neutralize the nifurtimox- and benznidazole-derived metabolites by conjugation, producing drug–thiol conjugates that will be further metabolized to mercapturates in the mammal host. Free radicals are neutralized, and there is oxidation of reduced GSH or T(SH)₂. Trypanothione reductase reduces oxidized trypanothione (T(S)₂).