Seizure Protection by Intrapulmonary Delivery of Propofol Hemisuccinate

Abstract

The lung provides a portal of entry for drug delivery that could be used to administer anticonvulsant substances to prevent or abort seizures. Here, we demonstrate that intrapulmonary propofol hemisuccinate (PHS) rapidly confers seizure protection in various rodent chemoconvulsant models. Propofol is a powerful anticonvulsant substance at subanesthetic doses, but it is a viscous, water-immiscible oil that is not suitable for intrapulmonary administration. We found that PHS can be formulated as an aqueous solution that is well tolerated when instilled into the lung. High-dose intraperitoneally administered PHS induced loss-of-righting reflex in rats and mice. The onset of action of PHS was delayed in comparison with propofol, suggesting that conversion to propofol is required for activity. A lower dose of PHS (40 mg/kg i.p.) did not cause general anesthesia but protected against pentylenetetrazol (PTZ)-induced seizures in rats. Intrapulmonary administration of an aqueous PHS solution via a tracheal cannula at lower doses (5 and 10 mg/kg) conferred equivalent seizure protection without acute motor toxicity. In mice, intraperitoneal PHS (60 -80 mg/kg) was associated with an elevation in PTZ, bicuculline, picrotoxin, and kainic acid seizure thresholds. Intratracheal PHS was markedly more potent, producing seizure threshold elevations at doses of 10 to 15 mg/kg. In the PTZ threshold model in mice, PHS was active at 5 min, maximally active at 10 min, and no longer active at 20 min. Intratracheal PHS also prolonged the onset of 4-aminopyridine-induced convulsions but did not affect the threshold for N-methyl-D-aspartate-induced convulsions. We conclude that intratracheal administration of an aqueous solution of PHS, a putative propofol prodrug, provides potent seizure protection of rapid onset and brief duration. Intrapulmonary PHS may be useful for preventing the spread of seizures or aborting seizure clusters without causing prolonged sedation.

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

“…Our demonstration that intraventricular TETS causes a similar behavioral response and lethality as with systemic administration supports this conclusion. The seizures induced by TETS seem similar to those produced by GABA antagonists such as PTZ and picrotoxin (Dhir et al, 2011). The rate of onset of seizures induced by low sublethal doses of TETS was similar to that of picrotoxin but slower than for PTZ.…”

“…The rate of onset of seizures induced by low sublethal doses of TETS was similar to that of picrotoxin but slower than for PTZ. Therefore, to obtain accurate estimates of threshold values in the intravenous infusion model, slower infusions were required than is the case with PTZ (Dhir et al, 2011). With higher (lethal) doses the latency was reduced and seizures occurred rapidly.…”

The Epilepsy Foundation's 4th Biennial Epilepsy Pipeline Update Conference

“…The concept is that PHS would be self-administered during a seizure aura to prevent the localized seizure discharge from progressing to a full-blown seizure or by a caregiver to terminate seizure clusters or status epilepticus. Animal studies have shown that intrapulmonary PHS has potent, broad-spectrum antiseizure activity [21]. Inhalation toxicology studies in rats demonstrated that intratracheal PHS does not cause histopathological changes in the lung.…”

Transdermal Iontophoretic Delivery of Propofol: A General Anaesthetic in the Form of its Phosphate Salt

“…Therefore, there is a need for development of alternate mode of delivery to avoid the side effects associated with the parenteral invasive mode of administration. Because propofol is viscous and water immiscible, pulmonary delivery is not possible 13. Oral route is not preferred for propofol administration either, as the hepatic extraction ratio of propofol was reported to be approximately 80%–90% 14.…”

“…Because propofol is viscous and water immiscible, pulmonary delivery is not possible. 13 Oral route is not preferred for propofol administration either, as the hepatic extraction ratio of propofol was reported to be approximately 80%-90%. 14 Moreover, it is not practical to administer maintenance doses of propofol when the patient has already been inducted with anesthesia.…”