Trypanosoma cruzi: In vitro effect of aspirin with nifurtimox and benznidazole.
Nifurtimox and benznidazole are the only active drugs against Trypanosoma cruzi; however, they have limited efficacy and severe side effects. During primoinfection, T. cruzi infected macrophages mount an antiparasitic response, which the parasite evades through an increase of tumor growth factor beta and PGE(2) activation as well as decreased iNOS activity. Thus, prostaglandin synthesis inhibition with aspirin might increase macrophage antiparasitic activity and increase nifurtimox and benznidazole effect. Aspirin alone demonstrated a low effect upon macrophage antiparasitic activity. However, isobolographic analysis of the combined effects of aspirin, nifurtimox and benznidazole indicated a synergistic effect on T. cruzi infection of RAW cells, with combinatory indexes of 0.71 and 0.61, respectively. The observed effect of aspirin upon T. cruzi infection was not related with the PGE(2) synthesis inhibition. Nevertheless, NO() levels were restored by aspirin in T. cruzi-infected RAW cells, contributing to macrophage antiparasitic activity improvement. Thus, the synergy of aspirin with nifurtimox and benznidazole is due to the capability of aspirin to increase antiparasitic activity of macrophages.
López-Muñoz
Rodrigo
R
Program of Molecular and Clinical Pharmacology, ICBM, School of Medicine, University of Chile, Chile.
Faúndez
Mario
M
Klein
Sebastián
S
Escanilla
Sebastián
S
Torres
Gloria
G
Lee-Liu
Dasfne
D
Ferreira
Jorge
J
Kemmerling
Ulrike
U
Orellana
Myriam
M
Morello
Antonio
A
Ferreira
Arturo
A
Maya
Juan D
JD
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D051379:Mice; D009547:Nifurtimox / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009593:Nitroimidazoles / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
D016861:Cyclooxygenase Inhibitors; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D009569:Nitric Oxide; D009547:Nifurtimox; D001241:Aspirin; C009999:benzonidazole