Evaluation of the protective effects of quinacrine against Bacillus anthracis Ames.
J Toxicol Environ Health A
; 69(11): 1083-95, 2006 Jun.
Article
em En
| MEDLINE
| ID: mdl-16840255
ABSTRACT
Bacillus anthracis has gained notoriety as a dangerous biological weapon because of its virulence and ability to produce highly resistant spores. In addition, the ability of this organism to produce plasmid-encoded edema toxin (EdTx) and lethal toxin (LeTx) plays a pivotal role in the pathogenesis of anthrax. In this study, the efficacy of quinacrine was evaluated against the effects of anthrax toxins in vitro and its ability to provide protection against challenge with B. anthracis Ames strain spores in an intranasal mouse and guinea pig model. Quinacrine protected murine macrophages in vitro against cytotoxicity and cAMP production induced by LeTx and EdTx, respectively, at concentrations of 40-80 microM, most likely by preventing acidification of the endosomes. However, animals dosed with human equivalent doses of quinacrine were not protected against respiratory spore challenge. The failure of quinacrine to provide protection against inhalation anthrax was attributed to our inability to attain inhibitory concentrations of the drug in the serum or tissues. After daily administration of 43.3 mg quinacrine to guinea pigs (300 g), serum levels after 96 h were only 9.9 microM, a concentration not sufficient to protect macrophages in vitro. Administration of high doses of quinacrine (86.6 mg/kg) was toxic to the animals. These results illustrate some of the difficulties in developing protective therapeutic strategies against inhalation anthrax even when antitoxic drugs appear effective in vitro.
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Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Quinacrina
/
Bacillus anthracis
/
Inibidores Enzimáticos
/
Antraz
Tipo de estudo:
Etiology_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Toxicol Environ Health A
Ano de publicação:
2006
Tipo de documento:
Article