Antiparasitic activity of risedronate in a murine model of acute Chagas' disease.
We report the results of a study on the activity of the farnesyl-pyrophosphate synthase inhibitor risedronate (Ris) in a murine model of acute Chagas' disease. This compound displays rapid, cytocidal activity in vitro against Trypanosoma cruzi, but its in vivo activity had not been investigated previously. A murine model of acute Chagas' disease was used, in which experimental animals were infected with 10(3) trypomastigotes and intravenous treatment was started 24 h post-infection. In this model, Ris, at doses as low as 1 mg/kg per day given for 7 days, induced > 90% reductions in parasitaemia and increased very significantly (P = 0.001) the survival of treated animals. Higher doses (up to 10 mg/kg per day) led to further reductions in parasitaemia and mortality, with no deleterious effects on weight gain and general physical condition of the treated animals. There was no relapse of parasitaemia after discontinuation of treatment, suggesting trypanocidal, rather than trypanostatic, activity. This interpretation was confirmed by the almost complete disappearance of amastigote nests in the hearts of treated animals. However, no parasitological cures were observed in infected animals that received the bisphosphonate, probably due to the short treatment period. Taken together, these results indicate that Ris could be a useful lead compound for the development of new drugs effective against Chagas' disease.
Garzoni
Luciana R
LR
Departmento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Av. Brasil, 4365 Manguinhos, 21045-900 Rio de Janeiro, RJ, Brazil.
Waghabi
Mariana C
MC
Baptista
Marcos M
MM
de Castro
Solange L
SL
Meirelles
Maria de Nazareth L
Mde N
Britto
Constança C
CC
Docampo
Roberto
R
Oldfield
Eric
E
Urbina
Julio A
JA
D000208:Acute Disease; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D051228:Geranyltranstransferase; D006321:Heart / Q000469:parasitology; D051379:Mice; D009206:Myocardium / Q000473:pathology; D018512:Parasitemia / Q000188:drug therapy; D000068296:Risedronic Acid; D014344:Trypanocidal Agents / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D000068296:Risedronic Acid; D012968:Etidronic Acid