Abstracts

RATIONALE: Refractory epilepsy is a significant clinical problem that requires the development of a rational basis for the use of existing antiepileptic drugs (AEDs), particularly in polypharmacy regimens. There is emerging evidence to support the efficacy of particular combinations of AEDs, although definitive clinical studies are difficult to perform. Experimental seizure models can be employed to identify potentially beneficial combinations for future evaluation in this patient population. The following studies were designed to investigate potential pharmacodynamic interactions between topiramate (TPM) and a range of established and modern AEDs.
METHODS: Adult male ICR mice were pre-treated with single doses (and combinations) of TPM (5, 25, 125 mg/kg) and adjunctive agent by intraperitoneal injection. The following adjunctive drugs were employed; phenobarbital (PB; 2, 10, 50 mg/kg), phenytoin (PHT; 2, 10, 50 mg/kg), primidone (PRM; 4, 20, 100 mg/kg), carbamazepine (CBZ; 2, 10, 50 mg/kg), ethosuximide (ESM; 25, 125, 625 mg/kg), sodium valproate (VPA; 40, 200, 1000 mg/kg), clobazam (CLB; 0.2, 1, 5 mg/kg), vigabatrin (VGB; 10, 50, 250 mg/kg), lamotrigine (LTG; 0.5, 2.5, 12.5 mg/kg), felbamate (FBM; 10, 50, 250 mg/kg), gabapentin (GBP; 5, 25, 125 mg/kg), tiagabine (TGB; 0.2, 1, 5 mg/kg) and levetiracetam (LEV; 10, 50, 250 mg/kg). Anticonvulsant effects of single doses and combinations were determined in the pentylenetetrazol (PTZ) and maximal electroshock (MES) seizure models at one hour post-dosing.
RESULTS: In the PTZ test, TPM was without significant effect. In contrast, PB, PRM, ESM, VPA, FBM and TGB all increased the latency to the first generalised seizure induced by 85mg/kg PTZ. Combinations of TPM and active adjunctive drug were universally effective in the PTZ test. In addition, combinations of TPM with CLB, LTG and LEV were anticonvulsant, despite the inactivity of the constituent compounds when administered alone. In the MES test, TPM reduced the incidence of tonic seizures in a dose-dependent manner. PB, PHT, PRM, CBZ, VPA, CLB, LTG, FBM and TGB were similarly effective, as were all combination treatments.
CONCLUSIONS: The findings of these exhaustive studies suggest that combinations of TPM with LTG and LEV may demonstrate anticonvulsant synergism and merit further detailed investigation in more appropriate model systems and with recourse to more quantitative mathematical analysis.
[Supported by: This study was supported by The RW Johnson Pharmaceutical Research Institute (Spring House, PA, USA).]; (Disclosure: Salary - None, Grant - GlaxoSmithKline Janssen-Cilag Sanofi-Synthelabo The RW Johnson Pharmaceutical Research Institute UCB Pharma, Equity - None, Consulting - GlaxoSmithKline Janssen-Cilag Pfizer UCB Pharma, Ownership - None, Materials - None, Stock - None, Royalties - None, Honoraria - GlaxoSmithKline Janssen-Cilag Pfizer Sanofi-Synthelabo UCB Pharma, Other - None)