Evaluaci\uf3n de la eficacia de la combinaci\uf3n de drogas tripanocidas, inmunoestimulantes y antioxidantes en ratones NMRI con enfermedad de chagas agudo

La enfermedad de Chagas, es producida por el par\ue1sito Trypanosoma cuzi, es una infecci\uf3n con una elevada morbimortalidad, cuya expresiones cl\uednicopatologicas m\ue1s graves son la miocarditis aguda y la cardiopat\ueda chag\ue1sica cr\uf3nica. Actualmente no existe tratamiento definitivo, por lo que el desarrollo de alternativas terap\ue9uticas es considerado una prioridad para los pa\uedses con alta incidencia y prevalencia de la enfermedad. La presente tesis tuvo como objetivo evaluar la eficacia terap\ue9utica de drogas tripanocidas, inmunoestimulantes y antioxidantes en ratones con enfermedad de Chagas en fase aguda. Se evaluaron las drogas nifurtimox, benznidazol, alopurinol, dipiridamol y melatonina, en modelos "in vitro" representados por curvas dosis-respuesta ensayadas en cultivos ax\ue9nicos de epim\ue1stigotes de Trypanosoma cruzi y en modelos "in vivo" evaluando la evoluci\uf3n cl\uednica, electrocardiogr\ue1fica, parasitol\uf3gica y bioqu\uedmica en ratones albinos de la cepa NMRI infectados con par\ue1sitos del linaje Tcl y tratados al comprobarse el pico de la parasitemia en la fase aguda. In vitro, nifurtimox fue la droga m\ue1s potente con una D150de 21.53 \ub1 2.13, le siguieron benznidazol, dipiridamol y melatonina con DI50 de 44.34 \ub1 5.98, 372 \ub152 Y 502,3 \ub1 90,1 \ub5M, respectivamente; todas las drogas ensayadas potenciaron la acci\uf3n de nifurtimox. In vivo nifurtimox 40 mg/kg s\uf3lo o en combinaci\uf3n melatonina, dipiridamol o alopurinol tuvo un efecto terap\ue9utico evidente reflejado en una supervivencia entre el 80 y 100 %, en la erradicaci\uf3n de la parasitemia y en la ausencia de amastigotes en el tejido card\uedaco. Nifurtimox a 10 mgfkg tuvo un efecto subterap\ue9utico con una supervivencia del 25 %, parasitemia ausente, persistencia de amastigotes (=3D2 por campo microsc\uf3pico) con infiltrado mononuclear y fibrosis en el tejido card\uedaco, esplenomegalia e incremento de TOO. Sin embargo, el efecto del nifurtimox fue potenciado por dipiridamol, ya que, se logr\uf3 erradicar la parasitemia, disminuir los amastigotes (<1 por campo microsc\uf3pico), el infiltrado mononuclear y la fibrosis en coraz\uf3n, la supervivencia fue del 80 %, y los valores de las enzim\ue1s TOO y CPKMB, y la esplenomegalia se normalizaron; mientras que la adici\uf3n de melatonina evit\uf3 el desarrollo de fibrosis y alopurinol no logr\uf3 potenciar el efecto de nifurtimox 10 mg/kg in vivo. Dipiridamol, melatonina y alopurinol no tuvieron por si solos efecto en la infecci\uf3n aguda. En conclusi\uf3n, la dosis terape\ufatica de nifurtimox es 40 mg/kg, mientras que dipridamol potencia el efecto de nifurtimox 10 mgfkg mejorando su perfil terap\ue9utico y melatonina previene el desarrollo de fibrosis

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

<div><p>Abstract Background: Chagas disease is a global health problem; therefore, the development of new therapeutic protocols is necessary. Our group recently demonstrated that nifurtimox associated with dipyridamole has curative effects in mice with acute Chagas disease. In this study, we assess the effect of this therapeutic protocol in chagasic mice with heart failure. Objective: To evaluate whether nifurtimox and dipyridamole are useful to rescue mice with severe acute chagasic myocarditis with heart failure. Methods: 42 mice with acute chagasic myocarditis and congestive heart failure were divided into three groups: control chagas (n = 11), Nif-Dip treated with nifurtimox and dipyridamole (n = 14) and Nif-Dip-heart failure treated with nifurtimox and dipyridamole associated with digoxin, furosemide, and captopril (n = 17). Nifurtimox and dipyridamole doses were 40 and 30 mg/kg/day, respectively, for 6 weeks. Mice underwent clinical, electrocardiographic, hemoparasitological and histopathological assessments. Results: Lower mortality in Nif-Dip (28.57%; n = 4) compared to control chagas (54.54%; n = 6) and Nif-Dip-heart failure (52.9%; n = 9) was observed. Clinically, nifurtimox and dipyridamole-treated mice increased body weight and improved heart failure without splenomegaly. In these groups, parasitemia and tissue parasites were eradicated; fibrosis, myocytolysis, inflammatory cell infiltrate and mast cells decreased. Repolarization disorders, prolonged QRS and QT intervals, increase of S wave amplitude and atrioventricular dissociation were reversed by the treatment. Conclusion: Nifurtimox with dipyridamole can rescue NMRI mice from severe acute chagas disease, as nifurtimox showed trypanocidal activity and dipyridamole potentiated its effect. Dipyridamole would be useful in chagasic heart failure.</p></div

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

<div><p> 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.</p></div