Effect of the Anti-depressant Sertraline, the Novel Anti-seizure Drug Vinpocetine and Several Conventional Antiepileptic Drugs on the Epileptiform EEG Activity Induced by 4-Aminopyridine.

Seizures are accompanied by an exacerbated activation of cerebral ion channels. 4-aminopyridine (4-AP) is a pro-convulsive agent which mechanism of action involves activation of Na(+) and Ca(2+) channels, and several antiepileptic drugs control seizures by reducing these channels permeability. The antidepressant, sertraline, and the anti-seizure drug vinpocetine are effective inhibitors of cerebral presynaptic Na(+) channels. Here the effectiveness of these compounds to prevent the epileptiform EEG activity induced by 4-AP was compared with the effectiveness of seven conventional antiepileptic drugs. For this purpose, EEG recordings before and at three intervals within the next 30 min following 4-AP (2.5 mg/kg, i.p.) were taken in anesthetized animals; and the EEG-highest peak amplitude values (HPAV) calculated. In control animals, the marked increase in the EEG-HPAV observed near 20 min following 4-AP reached its maximum at 30 min. Results show that this epileptiform EEG activity induced by 4-AP is prevented by sertraline and vinpocetine at a dose of 2.5 mg/kg, and by carbamazepine, phenytoin, lamotrigine and oxcarbazepine at a higher dose (25 mg/kg). In contrast, topiramate (25 mg/kg), valproate (100 mg/kg) and levetiracetam (100 mg/kg) failed to prevent the epileptiform EEG activity induced by 4-AP. It is concluded that 4-AP is a useful tool to elicit the mechanism of action of anti-seizure drugs at clinical meaningful doses. The particular efficacy of sertraline and vinpocetine to prevent seizures induced by 4-AP is explained by their high effectiveness to reduce brain presynaptic Na(+) and Ca(2+) channels permeability.

Once-daily dosing is appropriate for extended-release divalproex over a wide dose range, but not for enteric-coated, delayed-release divalproex: evidence via computer simulations and implications for epilepsy therapy.

Divalproex sodium extended-release (divalproex-ER), administered once-daily, maintains plasma valproic acid (VPA) concentrations for 24h, whereas enteric-coated, delayed-release divalproex sodium (divalproex) requires multiple-daily doses to do the same. We hypothesize that a once-daily divalproex regimen should not be administered to epilepsy patients requiring high total daily doses, e.g., 35.6-56 mg/kg/day, due to the potential for high (>125 mg/L) maximum VPA concentrations (C(max)). We examined the impact of once-daily dosing, divalproex vs. divalproex-ER, on steady-state plasma VPA concentration-time profiles at commonly used doses in monotherapy (uninduced) and polytherapy (hepatic enzyme-induced) virtual adult patients. Only the 1125 mg once-daily divalproex dose had mean C(max)<100mg/L; >or=2000 mg produced mean C(max)>or=125 mg/L. Mean divalproex C(min) was approximately 50 mg/L at two of four doses tested, whereas mean ER C(min) was >73 mg/L at all doses tested. Once-daily divalproex peak-trough fluctuation was 4.4-6.2-fold greater than once-daily divalproex-ER. We predict that excursions beyond the conventional recommended VPA plasma concentration range will commonly occur with high total mg daily doses (>or=2000 mg) of enteric-coated divalproex, if dosed once-daily, potentially producing clinical toxicity. This divalproex formulation should not be dosed once-daily at high total mg daily doses due to this risk. Divalproex-ER is the appropriate formulation for administration on a once-daily basis, especially if large total mg/day doses are required for the control of seizure activity.

A novel system allowing long-term simultaneous video-electroencephalography recording, drug infusion and blood sampling in rats.

INTRODUCTION: Electroencephalography (EEG) recording and drug administration is commonly used for neurological experiments in rats, but is typically cumbersome due the use of multiple lines. We have developed a unique system, which allows long-term simultaneous video-electroencephalography recording, drug infusion and blood sampling in rats. METHODS: The vEEG/drug infusion system was designed and tested on two contrasting animal models of epilepsy. Animals were implanted with EEG-electrodes and a jugular vein cannula fixed in a head cap, avoiding an additional cable for tethering. In an acute infusion study (n=16), repeated blood samples were taken after i.v. bolus injection of valproate. In a subset of these rats (n=10), paired blood samples were removed from the jugular vein and the heart after valproate administration. In a chronic infusion study (n=38), heparinised (4IU/h) saline or valproate (42mg/kg/h) was infused continuously for up to 17 days. RESULTS: In the acute study, repeated blood samples showed a decrease in plasma valproate levels over time following bolus injection. In the chronic study, high quality continuous EEG was achieved and 79% of animals were successfully infused throughout the planned infusion period (13-17 days), with 66% of projected blood samples able to be taken during the infusion. There was a high correlation between the jugular vein and cardiac plasma levels of valproate (Spearman test, r=0.69; p<0.05). CONCLUSION: This system is ideal for pharmacokinetic/dynamic studies and long-term drug infusion where simultaneous EEG and/or frequent blood sampling are desired.