Doheny, Helen Christine; (1999) Pharmacological and electrophysiological study of antiepileptic drugs in a chronic and acute model of epilepsy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The objectives of this theses were (i) to determine the kinetics of carbamazepine (CBZ), a well established antiepileptic drug and levetiracetam, a new antiepileptic drug presently undergoing clinical evaluation in a freely behaving rat model, (ii) to test the efficacy of these drugs on electrographic seizures in animals injected with tetanus toxin, and to determine the relationship between their efficacy and their corresponding concentrations in blood and cerebrospinal fluid (CSF), and finally (iii) to evaluate the antiepileptic properties of levetiracetam on bicuculline induced epileptiform bursts in the hippocampal slice. The first objective entailed the development of a freely behaving rat model which allowed concurrent blood and CSF sampling and consequently pharmacokinetic characteristics of a drug over a relatively chronic period (7 days). Under anaesthesia a cisterna magna catheter, for CSF sampling, a jugular vein catheter, for blood sampling, and an intraperitoneal osmotic minipump set to deliver CBZ or levetiracetam were implanted. CSF and blood samples were collected on days 1, 2, 4, 6 and 7 post-surgery at timed intervals and analysed for CBZ and carbamazepine epoxide (CBZ-E; the primary pharmacological active metabolite of CBZ) or levetiracetam content by high performance liquid chromatography. The serum and CSF concentration versus time profiles of CBZ and CBZ-E, exhibited biphasic characteristics; the first phase involved rapid appearance of CBZ and CBZ-E in blood and CSF compartments followed by a gradual increase until maximum concentrations were achieved. During the second phase, CBZ exhibited a marked acceleration in its metabolism (autoinduction), as indicated by a dramatic reduction and a subsequent gradual decline in both CBZ and CBZ-E blood and CSF concentrations. However, in contrast to CBZ, chronic levetiracetam administration was not associated with autoinduction. Following its acute and chronic administration, levetiracetam appeared in blood and CSF compartments and thereafter concentrations rose linearly until maximum concentrations were achieved. The second objective related to the efficacy of CBZ and levetiracetam in the in vivo tetanus toxin model of epilepsy. Under anaesthesia, tetanus toxin was injected, and a bipolar electrode placed in the hippocampus. Initial EEG recordings began 1-2 days post-surgery and continued for 5-7 days. A minipump with CBZ/levetiracetam was then implanted intraperitoneally and continuous EEG and video recordings were undertaken for a further 7 days. The animals developed a chronic limbic epilepsy, characterized by the occurrence of spontaneous interictal spikes, polyspikes, nongeneralised and generalised seizures. Both CBZ and levetiracetam exhibited efficacy in this model, involving a reduction in the maximum number of seizures occurring per day and a reduction in the total number of generalised seizures over the period analysed. However, a statistically significant result was only achieved following administration of the highest dose of levetiracetam (16 mg/kg/h; p=0.0004). Furthermore, at all doses studied a significant reduction in the duration of generalised seizures was observed following administration of CBZ (p<0.0001) and levetiracetam (p<0.0001). The final objective related to the efficacy of levetiracetam in an in vitro hippocampal slice model of epileptiform activity. Hippocampal slices were made epileptic via bath application of bicuculline and raised extracellular potassium. This activity took the form of trains of population bursts with a distinctive biphasic pattern lasting several seconds. Levetiracetam (200 and 400 μmol/1) significantly (p<0.0001) reduced the overall duration of these seizure-like events without influencing the biphasic pattern. In conclusion this thesis demonstrates that CBZ and levetiracetam possess different kinetic characteristics. Whilst CBZ exhibited complex and undesirable kinetics, levetiracetams were simple and predictable. Additionally, although CBZ and levetiracetam significantly reduced seizure generalisation in vivo, a statistically significant reduction was only achieved with the highest levetiracetam dose studied. Levetiracetam also appeared to attenuate the prolonged ictalform discharges in the disinhibited in vitro slice. Overall, these findings suggest that whereas levetiracetam does not effect epileptogenesis per se it does reduce seizure severity and, particularly, seizure generalisation in vivo in predominantly disinhibitory models.

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