UCB 34714, A NEW PYRROLIDONE DERIVATIVE: COMPARISON WITH LEVETIRACETAM IN ANIMAL MODELS OF CHRONIC EPILEPSY [italic]IN VIVO[/italic]
Abstract number :
2.245
Submission category :
Year :
2003
Submission ID :
2163
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Alain Matagne, Benoit Kenda, Philippe Michel, Henrik Klitgaard Preclinical CNS Research, UCB S.A., Pharma Sector, Braine-l[apos]Alleud, Belgium; Chemistry Research, UCB S.A., Pharma Sector, Braine-l[apos]Alleud, Belgium
ucb 34714 is a new pyrrolidone derivative, structurally related to levetiracetam (LEV, Keppra[reg]) which displays higher affinity (pKi = 7.1) than LEV (pKi = 6.1) to the LEV-binding site. This study compared the antiseizure and antiepileptogenic activities of ucb 34714 and LEV in a variety of [italic]in vivo[/italic] models of epilepsy.
Antiseizure activity was assessed in corneally-kindled male NMRI mice (25-35g; n=10), hippocampal- and amygdala-kindled male Sprague Dawley rats (350-450g; n=8), audiogenic seizure prone male mice (20-25g; n=10) and in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). CNS adverse effects were quantified in the rotarod test. Antiepileptogenic activity was assessed against the development of corneal kindling in male NMRI mice (25-35g; n=20).
ucb 34714 displayed a more potent protection than LEV against secondarily generalised motor seizures in corneally-kindled mice (ED[sub]50[/sub] = 1.2 mg/kg vs. 7.3 mg/kg i.p.) and hippocampal-kindled rats (Minimal Active Dose = 0.21 mg/kg vs. 54 mg/kg p.o.) and against clonic convulsions in audiogenic susceptible mice (ED[sub]50[/sub] = 2.4 mg/kg vs. 30 mg/kg i.p.). Furthermore, ucb 34714 induced a more significant suppression than LEV of motor seizure severity and afterdischarge duration in amygdala-kindled rats and of spike-wave-discharges in GAERS. Safety margins of ucb 34714 and LEV (TD[sub]50[/sub]/ED[sub]50[/sub] values of rotarod impairment and seizure protection, respectively) in corneally-kindled mice (55 vs 148) and amygdala-kindled rats (4 vs 2) were relatively similar. Chronic treatment with LEV (1.7 [ndash] 54 mg/kg i.p.) and ten times lower doses of ucb 34714 (0.21-6.8 mg/kg i.p.) induced a similar suppression in the development of corneal kindling. However, continued corneal stimulations following termination of treatment revealed that ucb 34714 possesses a more persistent ability to counteract the kindling process.
This preclinical study showed that ucb 34714 is more potent and active than LEV as an antiseizure and antiepileptogenic agent in various [italic]in vivo[/italic] epilepsy models.
[Supported by: UCB S.A., Pharma Sector]