Dipyridamole potentiated the trypanocidal effect of nifurtimox and improved the cardiac function in NMRI mice with acute chagasic myocarditis

Abstract

BACKGROUND As chronic Chagas disease does not have a definitive treatment, the development of alternative therapeutic protocols is a priority. Dipyridamole (DPY) is an alternative to counteract the pathophysiological phenomena involved in Chagas cardiomyopathy.OBJECTIVE To evaluate the therapeutic efficacy of DPY associated with nifurtimox (Nfx) in epimastigote axenic cultures and in mice with acute Chagas disease.METHODS NMRI adult male mice were divided into nine groups: three healthy and six Trypanosoma cruzi-infected groups. Mice received vehicle, Nfx or DPY, alone or combined. The doses assayed were Nfx 10 and 40 mg/kg and DPY 30 mg/kg. The treatment efficacy was evaluated by clinical, electrocardiographic, parasitological, biochemical and histopathological methods.FINDINGS In vitro, DPY and Nfx had a trypanocidal effect with IC50 values of 372 ± 52 and 21.53 ± 2.13 µM, respectively; DPY potentiated the Nfx effect. In vivo, Nfx (40 mg/kg) with or without DPY had a therapeutic effect, which was reflected in the 84-92% survival rate and elimination of parasitaemia and heart tissue amastigotes. Nfx (10 mg/kg) had a subtherapeutic effect with no survival and persistence of amastigotes, inflammation and fibrosis in heart tissue; adding DPY increased the survival rate to 85%, and all tested parameters were significantly improved.MAIN CONCLUSION DPY has a trypanocidal effect in vitro and enhances the Nfx therapeutic effect in an in vivo murine model.

Rescue Therapy with Nifurtimox and Dipyridamole for Severe Acute Chagas Myocarditis with Congestive Heart Failure in NMRI Albino Mice

“…29 Likewise, the R wave amplitude was unchanged, which might be due to irreversible damage to the myocardial structure or it could reflect a net pharmacological effect due to dipyridamole-induced negative inotropic effect mediated by adenosine acting on A1 receptors. 9 Mast cell density in heart tissue histological sections was higher in the CC group when compared to the NifDip group. Mast cells are inflammatory cells that increase and trigger a series of responses to inflammatory and infectious stimuli involved in myocarditis and dilated cardiomyopathy pathogenesis; a correlation between the degree of fibrosis and mast cell density in hearts of patients with dilated cardiomyopathy with CHF has been reported.…”

“…9 However, we propose that dipyridamole most beneficial effect is functional and it is related to its action mechanism.…”

“…9 For this reason, in this study we consider whether a therapeutic rescue in acute chagasic myocarditis (AChM) animals with severe CHF can be performed with nifurtimox and dipyridamole, allowing a reduction in mortality and cardiac functional sequelae. They were subsequently sacrificed by exsanguination via cardiac puncture under anesthesia, followed by autopsy, when organs were removed and weighed, and samples for histopathology were collected.…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“… [ 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. …”

“…155 Table 4 shows other promising drug associations for the treatment of experimental T. cruzi infection. 87,90,154,164,[183][184][185][186][187][188][189][190][191][192][193][194]…”