title: Prevention of benznidazole-induced prolonging effect on the pentobarbital sleeping time of rats using different thiol-containing compounds.
abstract: Benznidazole (BZ) is a nitroimidazolic chemotherapeutic agent employed against the acute and indeterminate phase of Chagas' disease, a tropical sickness afflicting more than twenty million people in Latin America. BZ has serious toxic side effects forcing people to stop treatment. These effects were attributed to the nitroreductive metabolic activation of BZ to a hydronitroxide radical or the hydroxylamine, which would covalently bind to cellular components. One of these deleterious effects is the prolongation on the pentobarbital sleeping time of rats. This results from the covalent binding of BZ reactive metabolites, arisen during its nitroreductive metabolism, to the phospholipid component of the mixed function oxidase which biotransform the barbiturate. In this study, the potential ability of different thiol containing drugs to trap BZ reactive metabolites and to prevent BZ effect on the pentobarbital sleeping time was tested. Our HPLC studies evidenced that cysteine, N-acetylcysteine, penicillamine and glutathione were able to trap BZ reactive metabolites in vitro to produce one or two adducts. Reduced lipoic acid instead, decreased the intensity of the nitroreductive process without leading to detectable adducts. The in vivo administration of the thiol drugs, at dosage regimes available in literature, was able to markedly prevent the BZ prolongation effect on the sleeping time. Whether these thiols might prevent other BZ toxic effects without harming its chemotherapeutic actions remains to be established.
authors.affiliation: Centro de Investigaciones Toxicológicas-CITEFA/CONICET, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Montalto de Mecca
authors.forename: A S
authors.initials: AS
authors.lastname: Bernacchi
authors.forename: J A
authors.initials: JA
authors.lastname: Castro
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009593:Nitroimidazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D006993:Hypnotics and Sedatives; D007166:Immunosuppressive Agents; D009593:Nitroimidazoles; D013438:Sulfhydryl Compounds; D010424:Pentobarbital; C009999:benzonidazole