Interaction of flunarizine with sodium valproate or ethosuximide in gamahydroxybutyrate induced absence seizures in rats.

Sodium valproate(VPA), ethosuximide(ESM), 200 mg/kg ip and flunarizine (FLU) 5 or 10 mg/kg ip were first administered independently to rats in order to study their effects on behavioural and EEG aspects of spike and wave discharges (SWDs) induced by y- hydroxybutyrate (GHB,100 mg/kg ip). GHB treated rats show behavioural changes and concomitant repetitive EEG episodes of 7 to 9 Hz SWDs, mimicking human absence seizures (AS), and can be used as a pharmacological model. The number and duration of SWDs were calculated for 1 hr from the EEG and were parameters for drug evaluation. VPA and ESM at 200 mg/kg, significantly reduced SWD number and duration/hr, while FLU showed significant reduction only at 10 but not at 5 mg/kg. Combination of FLU, 10 mg/kg with either VPA or ESM showed significant reduction of SWD number and duration, suggesting an additive effect of the anti-absence agents with the calcium channel blocker, FLU, on experimental absence seizures in rats.

Comparative profiles of sodium valproate and ethosuximide on electro-behavioural correlates in gamma-hydroxybutyrate and pentylenetetrazol induced absence seizures in rats.

Sodium valproate (VPA) and ethosuximide (ESM) were compared on behavioural and EEG changes in gamma-hydroxybutyrate (GHB) and pentylenetetrazole (PTZ) rat models of Absence Seizures (AS). Both GHB, 100 mg/kg i.p. and PTZ, 20 mg/kg i.p., produced repetitive episodes of staring and immobility with concomitant 6 to 9 Hz spike and wave discharges (SWDs) in the EEG. The parameters used for drug evaluation were the number and duration of SWDs/hour. Though the number of SWDs/hour produced by GHB and PTZ were not significantly different, the duration of SWDs was significantly longer in GHB treated rats (P < 0.001) VPA and ESM, at 200 mg/kg i.p., reduced SWD number and duration in GHB pretreated rats, whereas ESM, 50 mg/kg i.p., was four times more effective than VPA, 200 mg/kg i.p., in the PTZ model. Phenytoin (PHY) 20 and Carbamazepine (CBZ) 10 mg/kg i.p., worsened AS, a feature which has also been reported clinically. Both rat models of experimental AS can be used to defect potential anti-absence activity in new chemical entities.

Effect of sodium valproate and flunarizine administered alone and in combination on pentylenetetrazole model of absence seizures in rat.

Sodium valproate (VPA) and flunarizine (FLU) administered individually and together were examined for their effects on behavioural, and EEG changes in the pentylenetetrazole (PTZ) induced rat model of absence seizures. PTZ, 20 mg/kg, i.p., produced behavioural staring and immobility with concomitant, repetitive 7 to 9 Hz spike/wave discharges (SWDs) in EEG, monitored continuously for 1 hr and thereafter, intermittently for 4 hr, post-vehicle/drug. The number and duration (sec) of SWDs/hr were the parameters used for evaluation of vehicle vs. drug effects in normal as well as rats made epileptogenic by repeated cortical stimulation. VPA, 200 mg/kg, i.p., produced a significant reduction in the number and duration of SWDs at 20 min only in epileptogenic rats, declining to non-significant levels at 60 min, whereas FLU, 10 mg/kg i.p. had no effect on either parameter. The combination of VPA and FLU produced a highly significant reduction of the number and duration of SWDs/h for 60 min in normal and epileptogenic rats. The results provide evidence for a synergistic effect of VPA and FLU in experimental absence seizures and possible potential benefit in pharmaco resistant seizures.