Abstracts

Rationale: Patients suffering from mesial temporal lobe epilepsy frequently exhibit auras that may include somatosensory and special sensory phenomena (such as the perception of an unpleasant smell, visual distortions or auditory hallucinations), psychic phenomena ( feelings of fear or anxiety) or autonomic phenomena (epigastric rising or nausea). Administration of a rapidly-acting anticonvulsant at this stage may prevent the onset of a full-blown seizure. We have investigated the potential utility of propofol analogs delivered by the pulmonary route in this application. Propofol is a powerful anticonvulsant with a rapid onset of action and the additional advantage that its effects rapidly dissipate so that sedative side effects would rapidly resolve. Like intranasal administration, inhalation allows for self-administration but uptake into the circulation can be far more rapid and greater drug quantities can be delivered. Propofol is a viscous liquid that cannot be administered into the lungs. Methods: We have explored the anticonvulsant actions of water soluble prodrug forms of propofol, such as propofol hemisuccinate (PHS), as an alternative to propofol for intrapulmonary delivery. Results: Intraperitoneal administration of PHS (40-80 mg/kg) in rats protected against PTZ (80mg/kg., i.p.)-induced convulsions and raised the threshold for i.v. PTZ-induced myoclonic jerks, clonus and tonic extension. Intratracheal administration of an aqueous PHS solution via a tracheal cannula was markedly more potent in protecting against PTZ convulsions; complete seizure protection was obtained within minutes at doses of 5-10 mg/kg. Intratracheal delivery of cresyl violet dye revealed uniform distribution of the solution throughout the lungs. Conclusions: We conclude that intratracheal administration of an aqueous solution of PHS provides potent and rapid seizure protection, indicating that intrapulmonary PHS enters the alveoli and is rapidly absorbed into the blood stream and delivered to the brain. PHS is a candidate agent as an inhaled treatment to abort seizures in patients who experience seizure aura. Acknowledgment: Supported by the Epilepsy Research Foundation.