Levetiracetam Enhances Markedly the Seizure Suppression of Other Antiepileptic Drugs in Audiogenic Susceptible Mice
Abstract number :
1.257
Submission category :
Year :
2001
Submission ID :
2739
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
A.C. Matagne, MSc, Preclinical CNS Research, UCB SA, Pharma Sector, Braine l[ssquote]Alleud, Belgium; E. Baltes, Biochem. Eng., Drug Metabolism and Pharmacokinetics, UCB SA, Pharma Sector, Braine l[ssquote]Alleud, Belgium; R. Coupez, Drug Metabolism and P
RATIONALE: Approximately 30% of patients with epilepsy are not adequately controlled by use of antiepileptic drug (AED) monotherapy and invariable require polytherapy. Consequently, the combined action of AEDs is a subject of major importance, not only in relation to seizure control, but also in relation to avoiding untoward adverse effects. This study investigated the anticonvulsant, adverse and pharmacokinetic effects of combination therapy between the AED levetiracetam (LEV) and some of the classical AEDs, using a preclinical paradigm.
METHODS: All experiments were conducted on male audiogenic susceptible mice (n=10). Anticonvulsant effects were assessed by protective ED[sub]50[/sub] values against clonic convulsions. Changes in [italic]anticonvulsant[/italic] potency were expressed by the ratio between the ED[sub]50[/sub] value of the AED alone and the ED[sub]50[/sub] value obtained when combining different doses of the AED with a fixed ED[sub]25[/sub] dose of LEV (5.5 mg/kg ip). Adverse effects were determined by TD[sub]50[/sub] values for motor impairment in the rotarod test. Changes in [italic]adverse effect potential[/italic] were expressed by the ratio between the TD[sub]50[/sub] value of the AED alone and the TD[sub]50[/sub] value obtained when combining different doses of the AED with the same fixed dose of LEV (5.5 mg/kg ip). Plasma and brain AED levels were determined by GC, HPLC or FPIA analysis.
RESULTS: Combining LEV with valproate, clonazepam, phenobarbital, carbamazepine and phenytoin produced a marked increase in their anticonvulsant potency by a factor of 28, 23, 16, 4 and 2, respectively. Interestingly, LEV had no influence with any of the AEDs with regard to their adverse effect potential. Furthermore, plasma and brain levels of LEV and the AEDs were not modified during co-administration.
CONCLUSIONS: The present study demonstrates that LEV markedly enhances the anticonvulsant properties of various AEDs in audiogenic susceptible mice without having any concurrent effect on either their adverse effect potential or their plasma/brain levels. This supra-additive pharmacodynamic interaction suggests that the future medical management of epilepsy could benefit from combination therapy with LEV both in terms of efficacy and side-effect modulation of the existing AEDs.
Support: UCB SA.
Disclosure: Salary - Matagne -UCB SA; Baltez -UCB SA; Coupez -UCB SA; Klitgaard -UCB SA. Grant - Patsalos -UCB SA