Wang, Xiaolan; (2003) Neuropharmacological and kinetic correlates of antiepileptic drugs in an animal model of status epilepticus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Status epilepticus (SE) is considered to be one of the most severe forms of epilepsy with significant morbidity and mortality. There is a significant need for new drug treatments and this thesis sought to investigate the neuropharmacology of three new antiepileptic drugs (fosphenytoin [FosPHT], tiagabine [TGB] and topiramate [TPM]) in an animal model of SE. A freely moving rat model was first used to determine the temporal and concurrent kinetics of TGB and phenytoin (PHT; derived from FosPHT) in plasma, cerebrospinal fluid (CSF) and brain frontal cortex and hippocampal extracellular fluid (ECF). TGB displayed linear kinetics in blood and CSF compartment. Time to maximal concentration (Tmax) was achieved at a mean value of 16 0.3 minutes in the blood compartment, 32 0.9 minutes in CSF and 41 5 minutes and 34 3 minutes in brain frontal cortex and hippocampal ECF compartments, respectively. The equilibration between blood and CSF compartment was reached at 30 minutes postdose, whereas the ratio of TGB concentration between ECF and serum rose over time. Distribution in the brain ECF was not brain region specific. Elimination half-life (t1/2) values in blood and CSF compartment were similar (50 2.6 minutes and 64 2.7 minutes in blood and CSF compartments respectively), but were 3 times longer in brain ECF compartment (174 34 minutes and 134 9 minutes in frontal cortex and hippocampus respectively). FosPHT was rapidly metabolised to PHT and PHT displayed saturable kinetics in blood, CSF and brain ECF compartments. PHT rapidly penetrated the blood-brain barrier with a mean Tmax value of 12 1 minutes in CSF, 29 4 minutes and 34 3 minutes in frontal cortex and hippocampus respectively. Equilibration between blood and CSF and brain ECF compartments was reached by 15-30 minutes postdose. Distribution in the brain ECF was not brain region specific. t1/2 values were 266 64 minutes and 222 70 minutes in brain frontal cortex and hippocampus respectively. Comparison of the pharmacokinetics and neuropharmacokinetics of PHT after FosPHT and PHT administration revealed comparable results. A perforant path stimulation model of SE was used to explore the efficacy of FosPHT, TGB and TPM in suppressing seizures and protecting the brain from cell damage. Histopathological correlates (neuronal cell density), using Nissl staining, were used to identify any drug-related neuroprotective effects. Whilst TGB (at 20 mg/kg and 40 mg/kg) exhibited a dose-dependent efficacy in that SE was arrested rapidly and completely after 40 mg/kg TGB administration, FosPHT (at 100 mg/kg) and TPM (at 80 mg/kg and 160 mg/kg) were without effect in aborting SE. However, FosPHT, but not TPM, was associated with a 50% reduction of seizure severity (as assessed by Racine scale and the EEG spike frequency and amplitude). Nevertheless, none of these drugs were associated with any neuroprotection. Using microdialysis, amino acid neurotransmitters (e.g. glutamate, ?- aminobutyric acid [GABA], and taurine) were concurrently monitored in brain ECF before and during perforant path stimulation and self-sustained SE (SSSE). GABA concentrations rose whilst glutamate and taurine concentrations fell during perforant path stimulation. In contrast, during the period post perforant path stimulation and during SSSE there was a tendency for glutamate and GABA concentrations to return to baseline level, while taurine concentrations remained suppressed. In summary, both PHT, derived from FosPHT, and TGB have favourable kinetic features (rapid brain penetration, short Tmax at the site of drug action and slow elimination from the brain), which would be useful for the management of SE; TGB, but not FosPHT and TPM, is effective in the treatment of severe experimental refractory SE; TGB, FosPHT and TPM are without any neuroprotective properties as measured by the degree of protection from the loss of hippocampal neuronal cells in CA1, CA3 and hilus regions; the imbalance between brain excitatory and inhibitory neurotransmitters may underlie seizure occurrence and SE.

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