Abstract Details

Title Tonabersat, a Novel Investigational Anti-Seizure Drug, Inhibits Seizures in Models of Generalized Epilepsy

Topic Epilepsy

Presentation(s) P02 - (-)

Poster/Presentation
Number 209

Objective

Background BACKGROUND: Tonabersat, one of a series of compounds believed to have a novel mechanism of action via selective modulation of gap junctions, was initially developed for the treatment of migraine and epilepsy. Carabersat, a close analogue of tonabersat with a 3-4X lower affinity for the same binding site, was shown to be efficacious as adjunctive therapy for partial onset seizure (POS) in a clinical proof-of-concept study. As such, there exists a strong likelihood that tonabersat may exhibit anti-seizure properties.

Design/Methods DESIGN/METHODS: The anti-seizure profile of tonabersat was evaluated in a number of standard rodent models, in vitro and in vivo. CNS toxicity was assessed using the minimal motor impairment scale (rats) or rotarod test (mice). Probit analysis yielded the median effective (ED50) and toxic doses (TD50) at time of peak anti-seizure effect and therapeutic index (TI=[TD50/ED50]) was calculated for effective doses.

Results RESULTS: In vitro, tonabersat exhibited a concentration-dependent inhibition of electrographic bursting in the K+ hippocampal brain slice model (IC50=0.5[micro]M; 4X carbamazepine potency). In vivo, tonabersat significantly increased the threshold for electrically induced tonic extension seizures with a TI >36 (mice) and >240 (rats), but did not inhibit fully expressed seizures in hippocampal- or lamotrigine-resistant kindled rats after supra-maximal stimulation. Although tonabersat did not protect against limbic or generalized myoclonic seizures, it was effective against audiogenic seizures (AGS) in the Frings AGS-susceptible mouse (TI>2000). Additionally, tonabersat attenuated tonic seizures induced with continuous IV-pentylenetetrazol in both mice and rats. Further, at high tonabersat doses motor impairment was not observed (TD50 >250mg/kg [mice] and >500mg/kg [rats]).

Conclusions CONCLUSIONS: Tonabersat displayed a robust anti-seizure profile with a high TI in animal models. Its ability to prevent seizure spread in models of generalized epilepsy strongly suggests a therapeutic potential for generalized tonic-clonic seizures, complex partial seizures secondarily generalized, and/or POS.

Authors/Disclosures
Peter Blower, PhD PRESENTER	No disclosure on file
Tiago Mestre, MD, MSC (University of Ottawa)	Dr. Mestre has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CHDI. Dr. Mestre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC. Dr. Mestre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Dr. Mestre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ipsen. Dr. Mestre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Dr. Mestre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Mestre has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. The institution of Dr. Mestre has received research support from CIHR. The institution of Dr. Mestre has received research support from Ontario Research Fund. The institution of Dr. Mestre has received research support from MJFF. The institution of Dr. Mestre has received research support from Parkinson Canada. The institution of Dr. Mestre has received research support from University of Ottawa/PRC.
H. S. White, PhD (University of Utah)	No disclosure on file
	No disclosure on file

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