Epilepsy research
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Multicenter Study Clinical Trial
Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate.
To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. ⋯ Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.
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Developmental glioneuronal lesions, such as gangliogliomas (GG) are increasingly recognized causes of chronic pharmaco-resistant epilepsy. It has been postulated that chronic epilepsy in patients with malformations of cortical development is associated with dysfunction of the inhibitory GABA-ergic system. We aimed to identify the subtypes of interneurons present within GG specimens and the expression and cellular distribution patterns of GABA receptors (GABAR) and GABA transporter 1 (GAT1). ⋯ Compared to normal cortex, the density of PV- and CB-immunoreactive interneurons was reduced in the perilesional cortex of GG patients, whereas CR-labeling was similar to that observed in normal cortex. GAT-1 IR was also significantly reduced in the perilesional specimens. The cellular distribution of components of the GABA-ergic system in GG, together with the perilesional changes suggest that alterations of the GABA-ergic system may contribute to the complex abnormal functional network of these highly epileptogenic developmental lesions.
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Comparative Study
Effect of novel AMPA antagonist, NS1209, on status epilepticus. An experimental study in rat.
The current first line treatment of status epilepticus (SE) is based on the use of compounds that enhance GABAergic transmission or block sodium channels. These treatments discontinue SE in only two-thirds of patients, and therefore new therapeutic approaches are needed. We investigated whether a novel water-soluble AMPA antagonist, NS1209, discontinues SE in adult rats. ⋯ By using the administration protocols described, the anticonvulsant effect of NS1209 was faster and more complete than that of DZP. NS1209 treatment (20 mg/kg bolus followed by 5mg/kg h infusion for 24 h) was neuroprotective against SE-induced hippocampal neurodegeneration, but to a lesser extent than DZP. These findings suggest that AMPA receptor blockade by NS1209 provides a novel and mechanistically complimentary addition to the armamentarium of drugs used to treat SE in humans.
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Non-convulsive status epilepticus (NCSE) is characterized by continuous or recurrent, generalized or focal epileptiform activity on the electroencephalogram and diverse clinical symptoms with alterations of mental state and vigilance. NCSE is not rare but certainly under diagnosed. There is some debate about how aggressive NCSE should be treated, as high dose anticonvulsants maybe partially responsible for the morbidity and mortality of patients with NCSE. ⋯ We found no significant differences in hospitalisation time, time in intensive care unit and outcome between the LEV group and the control group. This retrospectively acquired data suggests that LEV may be a well tolerated, effective treatment option in NCSE. This highlights the need for a prospective controlled study to further elucidate the utility of LEV in the treatment of NCSE, particularly as an intravenous formulation is now available.
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Pregabalin (Lyrica) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. ⋯ Several studies indicate that the pharmacology of pregabalin requires binding to alpha2-delta subunits, including structure-activity analyses of compounds binding to alpha2-delta subunits and pharmacology in mice deficient in binding at the alpha2-delta Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.