Table 4.
Promising Drug Combinations in Experimental Treatment of Chagas Disease
| Combination | Outcome | References |
|---|---|---|
| BNZ/VFV | Combination presented promising results on parasitic blood load and cure levels in infected mice. | [119] |
| BNZ/itraconazole | Combination improved parasitemia reduction and total survival, reduced heart qPCR positivity and cardiac damage in VL-10-infected dogs. Itraconazole improved plasma concentration of BNZ. Combination led to an improvement in parasitemia reduction, and cardiac damage in infected mice. |
[176,178] [177] [157] |
| BNZ/ketoconazole | Combination induced a synergic effect in mice infected with CL and Y T. cruzi strains, but no differences were observed in Colombian strain-infected animals. | [150] |
| BNZ/fosravuconazole | In vitro interaction was positive and in infected mice. Early treatment induced 100% of cure and beneficial effect on well-established infection. | [118] |
| BNZ/posaconazole | Shorter duration of the treatment with combination induced cure in acutely or chronically Tulahen-infected mice but did not improve the curative effect of posaconazole in Y strain infection. Sequential and combined treatments were beneficial in murine infection, decreasing the time or dose of the BNZ treatment. Combination showed same efficacy of each drug alone in Colombian strain-infected mice and improved efficacy in Brazil strain-infected mice. Treatment of acute murine infection with the combination was more effective in reducing parasitemia and myocardial injury, compared to monotherapies. |
[155] [156] [56] [179] |
| BNZ/voriconazole | In vitro results indicated an additive interaction. In vivo, all treatments were well tolerated, and combination elicited no additional benefits over BNZ alone. | [180] |
| BNZ/arylimidamides | Trypanocidal activity was improved by combination therapies (BNZ plus DB766, DB289 or DB1965) in infected mice. | [87,90] |
| BNZ/allopurinol | Allopurinol combined with low dose of BNZ had a positive interaction on serology and pathology of infected mice. Sequential treatment exhibited beneficial effects on acute and chronic infection in mice. Allopurinol plus NFX or BNZ showed in vitro synergic effect. 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. | [188] |
| BNZ/acetyl salicylic acid | Aspirin combined with lower dosages of BNZ showed better therapeutic effect in infected mice. | [193] |
| BNZ/clomipramine | Clomipramine improved BNZ activity in vitro and in vivo with no cell toxicity and fewer side effects | [184,189] |
| BNZ/fenofibrate | Fenofibrate plus a low dose of BNZ attenuated cardiac dysfunction and promoted parasite clearance in mice sequentially infected with two strains of different genetic backgrounds. | [185] |
| BNZ/levamisole | Monotherapies of levamisole did not decrease parasitemia nor mortality rates. In combinations with a low dose of BNZ, it led to a slight improvement in the effectiveness of monotherapy | [192] |
| BNZ/NFX | Combining shorter treatments could cure mice, but the association led to the behavioral alterations of treated mice. | [155] |
| BNZ/simvastatin | Simvastatin improved BNZ activity in murine model of Chagas heart disease | [186] |
| BNZ/clofazimine or BNZ/benidipine | Reduced dose of 30mg/kg of BNZ associated with both drugs had the same efficacy as single 75mg/kg of BNZ in chronic model of Chagas disease in mice with no cure. | [164] |
| Itraconazole/amiodarone | The combination was benefic in infected dogs compared to non-treated control. The combinations were more effective in vitro T. cruzi-infection than monotherapy or BNZ; without affecting host cell metabolism and better preserving the integrity of infected cells. |
[190] [191] |
| Posaconazole/amiodarone | Amiodarone has direct in vitro and in vivo activity against T. cruzi and showed synergic effect with posaconazole. In vitro association improved IC50 and lead alterations in the parasite. |
[154] [183] |
| Ravuconazole/amlodipine | In vitro assays showed an additive effect for the combination. Amlodipine improved anti-T. cruzi activity of ravuconazole in infected mice. | [194] |
| NFX/dipyridamole | Dipyridamole potentiated the in vitro effect of NFX and improved efficacy of low dose of NFX in murine model. | [187] |
Abbreviations: BNZ, benznidazole; NFX, nifurtimox.