Synergic Effect of Allopurinol in Combination with Nitroheterocyclic Compounds against Trypanosoma cruzi

Abstract

Combination therapy has gained attention as a possible strategy for overcoming the limitations of the present therapeutic arsenal for Chagas disease. The aim of this study was to evaluate the effect of allopurinol in association with nitroheterocyclic compounds on infection with the Y strain of Trypanosoma cruzi. The in vitro effect of allopurinol plus benznidazole or nifurtimox on intracellular amastigotes in infected H9c2 cells was assessed in a 72-h assay. The interactions were classified as synergic for both allopurinol-nifurtimox (sums of fractional inhibitory concentrations [∑FICs] = 0.49 ± 0.08) and allopurinol-benznidazole (∑FICs = 0.48 ± 0.09). In the next step, infected Swiss mice were treated with allopurinol at 30, 60, and 90 mg/kg of body weight and with benznidazole at 25, 50, and 75 mg/kg in monotherapy and in combination at the same doses; as a reference treatment, another group of animals received benznidazole at 100 mg/kg. Allopurinol in monotherapy led to a smaller or nil effect in the reduction of parasite load and mortality rate. Treatment with benznidazole at suboptimal doses induced a transient suppression of parasitaemia with subsequent relapse in all animals treated with 25 and 50 mg/kg and in 80% of those that received 75 mg/kg. Administration of the drugs in combination significantly increased the cure rate to 60 to 100% among mice treated with benznidazole at 75 mg/kg plus 30, 60, or 90 mg/kg of allopurinol. These results show a positive interaction between allopurinol and benznidazole, and since both drugs are commercially available, their use in combination may be considered for the assessment in the treatment of Chagas disease patients.

Amlodipine Increases the Therapeutic Potential of Ravuconazole upon Trypanosoma cruzi Infection

“…Accumulating evidence has indicated that combination therapy is a promising approach to achieve a better response in the treatment of T. cruzi experimental infection (5,9,16,(22)(23)(24). In this context, a proof-of-concept evaluation of new benznidazole-sparing regimens in combination with E1224 and in monotherapy is ongoing.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…Journal of Experimental Pharmacology 2021:13 in T. cruzi infection outcome. 172,181 Sequential treatment with allopurinol and BNZ was able to reduce parasitemia and attenuate tissue damage in infected mice. 182 Generally, drug association allows to decrease the duration of the treatment limiting adverse effects related to time-dependent drug accumulation.…”

“… 169–171 Differently, Mazzeti et al demonstrated that this drug did not affect the evolution of Y acute infection in mice. 172 …”

“…The combinations increased the cure rate compared to BNZ alone in murine infection. [ 181 ] [ 182 ] [ 172 ] BNZ/ascorbic acid Ascorbic acid combined with a low dose of BNZ improved its trypanocidal activity and attenuated the toxic effects of BNZ. Combination also reduced cardiac inflammation and hepatic damage.…”

“…[169][170][171] Differently, Mazzeti et al demonstrated that this drug did not affect the evolution of Y acute infection in mice. 172 Other drug tested using repositioning strategy are the antiarrhythmic amiodarone, 154 auranofin 173 and clomipramine, 174,175 which were also active against T. cruzi in preclinical experimental infections (see Table 3). Amiodarone and miltefosine have mechanisms of action related to disruption of calcium homeostasis in T. cruzi.…”