title: In vitro and in vivo trypanocidal effects of the cyclopalladated compound 7a, a drug candidate for treatment of Chagas' disease.
abstract: Chagas' disease, a neglected tropical infection, affects about 18 million people, and 100 million are at risk. The only drug available, benznidazole, is effective in the acute form and in the early chronic form, but its efficacy and tolerance are inversely related to the age of the patients. Side effects are frequent in elderly patients. The search for new drugs is thus warranted. In the present study we evaluated the in vitro and in vivo effect of a cyclopalladated compound (7a) against Trypanosoma cruzi, the agent of Chagas' disease. The 7a compound inhibits trypomastigote cell invasion, decreases intracellular amastigote proliferation, and is very effective as a trypanocidal drug in vivo, even at very low dosages. It was 340-fold more cytotoxic to parasites than to mammalian cells and was more effective than benznidazole in all in vitro and in vivo experiments. The 7a cyclopalladate complex exerts an apoptosis-like death in T. cruzi trypomastigote forms and causes mitochondrion disruption seen by electron microscopy.
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo, SP 04023-062 Brazil. almatsuo@unifesp.br
authors.forename: Alisson L
authors.initials: AL
authors.lastname: Matsuo
authors.forename: Luis S
authors.initials: LS
authors.lastname: Silva
authors.forename: Ana C
authors.initials: AC
authors.lastname: Torrecilhas
authors.forename: Bruno S
authors.initials: BS
authors.lastname: Pascoalino
authors.forename: Thiago C
authors.initials: TC
authors.lastname: Ramos
authors.forename: Elaine G
authors.initials: EG
authors.lastname: Rodrigues
authors.forename: Sergio
authors.initials: S
authors.lastname: Schenkman
authors.forename: Antonio C F
authors.initials: AC
authors.lastname: Caires
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Travassos
mesh_terms: D000818:Animals; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010165:Palladium / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D021261:Parasitic Sensitivity Tests; D016896:Treatment Outcome; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity / Q000648:ultrastructure
chemical_list: D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D010165:Palladium; C009999:benzonidazole