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1.
Toxicol Lett ; 329: 26-30, 2020 Sep 01.
Article de Anglais | MEDLINE | ID: mdl-32380124

RÉSUMÉ

QF-036 is a novel human immunodeficiency virus (HIV) maturation inhibitor that is a lupine triterpenoid derivative. The objective of this study was to evaluate the safety of QF-036. A single oral toxicity and a 4-week repeated oral toxicity were investigated in Sprague-Dawley (SD) rats. The single oral toxicity study of QF-036 in SD rats showed that no mortality or visible pathological changes were noted at doses of 100, 300, and 1000 mg/kg. QF-036 exhibited a non-linear toxicokinetic profile over the dose range of 100-1000 mg/kg in the single dose study, and a saturation trend appeared at doses of 100 and 300 mg/kg. In the 4-week oral toxicity and toxicokinetic study, SD rats were given 0, 50, 100, and 200 mg/kg QF-036 once daily for 4 weeks, followed by a 4-week recovery period. No mortality or significant effects on food consumption, body weight, or behavior were observed. In addition, there were no test article-related changes in hematology, clinical biochemistry and histopathology. The no observed adverse effect level (NOAEL) was 200 mg/kg. The toxicokinetic study demonstrated a dose-dependent increase in the systemic exposure to QF-036 after 4 weeks of oral administration. There were no marked sex differences or drug accumulation observed for repeated doses of QF-036.


Sujet(s)
Agents antiVIH/toxicité , Triterpènes/pharmacologie , Administration par voie orale , Animaux , Agents antiVIH/administration et posologie , Agents antiVIH/composition chimique , Relation dose-effet des médicaments , Calendrier d'administration des médicaments , Femelle , Mâle , Structure moléculaire , Rats , Rat Sprague-Dawley , Tests de toxicité , Triterpènes/toxicité
2.
Hum Vaccin Immunother ; 16(1): 100-108, 2020.
Article de Anglais | MEDLINE | ID: mdl-31210561

RÉSUMÉ

Botulinum neurotoxins (BoNTs) are among the most toxic proteins. Vaccination is an effective strategy to prevent botulism. To generate a vaccine suitable for human use, a recombinant non-His-tagged isoform of the Hc domain of botulinum neurotoxin serotype E (rEHc) was expressed in Escherichia coli and purified by sequential chromatography. The immunogenicity of rEHc was evaluated in mice and dose- and time-dependent immune responses were observed in both antibody titers and protective potency. Then, the pilot-scale expression and purification of rEHc were performed, and its immunological activity was characterized. Our results showed rEHc has good immunogenicity and can elicit strong protective potency against botulinum neurotoxin serotype E (BoNT/E) in mice, indicating that rEHc is an effective botulism vaccine candidate. Further, we developed a novel antitoxin against BoNT/E by purifying F(ab')2 from pepsin-digested serum IgG of rEHc-inoculated horses. The protective effect of the F(ab')2 antitoxin was determined in vitro and in vivo. The results showed that our F(ab')2 antitoxin can prevent botulism in BoNT/E-challenged mice and effectively alleviate the progression of paralysis caused by BoNT/E to achieve therapeutic effects. Therefore, our results provide valuable experimental data for the production of a novel antitoxin, which is a promising candidate for the treatment of BoNT/E-induced botulism.


Sujet(s)
Antitoxines/immunologie , Vaccins antibactériens/immunologie , Toxines botuliniques/immunologie , Botulisme/prévention et contrôle , Animaux , Anticorps antibactériens/sang , Vaccins antibactériens/génétique , Botulisme/thérapie , Femelle , Equus caballus/immunologie , Immunogénicité des vaccins , Souris , Souris de lignée BALB C , Vaccination , Vaccins sous-unitaires/génétique , Vaccins sous-unitaires/immunologie , Vaccins synthétiques/immunologie
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