Abstracts

Rationale: Propofol (2,6-diisopropylphenol) is a powerful antiseizure agent that is effective in the treatment of drug refractory seizures at subanesthetic doses. However, propofol is poorly absorbed enterally precluding its use as an oral treatment agent. In this study, we sought to determine if the water soluble propofol prodrug, propofol hemisuccinate (PHS), which is de-esterified in the body to propofol, has oral antiseizure activity. Methods: PHS was administered by oral gavage in mice and assessed for protective activity in the maximal pentylenetetrazol (PTZ) test (PTZ dose, 80 mg/kg, i.p.) and in the timed PTZ infusion test. Plasma levels of propofol in mice were estimated by LC/MS. Results: When administered orally at doses of 80-150 mg/kg in the maximal PTZ test, PHS caused a dose-dependent increase in the time to onset or eliminated various seizure signs and protected against lethality. The most pronounced effect was in abolishing tonic extension. PHS was active at 15 min, indicating rapid conversion of PHS to propofol. PHS at a dose of 100 mg/kg, p.o. was also effective in elevating the seizure threshold in the timed infusion test. At that dose, PHS was devoid of any sedative effect as assessed using the inverted screen test. Oral doses of PHS (80-100 mg/kg) in mice were associated with plasma propofol levels of 700-900 ng/ml. Conclusions: PHS is a potent antiseizure agent when administered orally in mice and has potential as an oral agent in the acute treatment of seizures. Funding: None