Multiparticulate Drug Delivery Systems Preserve the Efficacy of Reduced-Dose Intermittent Benznidazole Therapy in Experimental Chagas Disease.

Chagas disease, caused by the Trypanosoma cruzi parasite infection, is primarily treated with benznidazole (BZ), though continuous dosing regimens are limited by adverse effects that compromise adherence. We evaluated whether a reduced-dose intermittent BZ regimen (50 mg/kg every 2 days, 20 doses), administered as free drug or incorporated into a BZ-loaded multiparticulate drug delivery system (BZ-MDDS), with or without adjunctive CD73 inhibition (APCP), maintains therapeutic efficacy and improves tissue-level safety in an experimental model of infection. Survival, parasitemia, cardiac parasite load, biochemical injury markers, and hepatic histology were assessed at 120 days post-infection (dpi), while echocardiographic parameters were recorded at 105 dpi. The reduced regimen markedly improved survival relative to untreated controls (p = 0.0001), with comparable terminal parasitological control across treated groups regardless of formulation or APCP co-administration. BZ-MDDS was associated with more preserved hepatic morphology and lower glutamate pyruvate transaminase elevation than free BZ (p < 0.05). Most cardiac, hepatic, and organ-weight parameters showed no significant differences between treated groups; pulmonary/aortic Doppler flow indices and visceral adipose tissue mass were the only parameters that differed, being lower in some treated groups relative to non-infected controls (p < 0.05 to p < 0.001). Together, these findings indicate that BZ-MDDS maintains the efficacy of a reduced-dose intermittent regimen with a favorable hepatic safety profile, although direct comparison with continuous standard-dose BZ was outside the scope of this study.