Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: a phase 1, randomized controlled study.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures. METHODS: This was a phase 1, randomized, placebo-controlled, parallel-group, escalating-dose, multiple-dose study comprising a 7-day, double-blind treatment period and a single-blind, single dose of pregabalin administered to all children on day 8. Children in four age cohorts (1-23 months, 2-6, 7-11, and 12-16 years) received one of four doses of pregabalin (2.5, 5, 10, or 15 mg/kg/day) or placebo. Safety and tolerability were assessed throughout the study. Steady-state and single-dose PK parameters on day 8 were analyzed using standard noncompartmental procedures. RESULTS: Sixty-five children received at least one dose of treatment. Four pregabalin-treated children discontinued treatment, three of whom received 15 mg/kg/day. Two children experienced serious adverse events, one of whom received pregabalin 15 mg/kg/day. During double-blind treatment, the most common adverse events reported in the pregabalin-treated population were somnolence (27.1%) and dizziness (12.5%). Steady-state pregabalin peak and total exposure in each age cohort appeared to increase linearly with dose. Apparent oral clearance (CL/F) was directly related to creatinine clearance, consistent with adults. CL/F normalized for body weight was 43% higher in patients weighing <30 kg. Steady-state and single-dose PK were consistent. SIGNIFICANCE: Pregabalin at doses up to 10 mg/kg/day in children aged 1 month to 16 years, and at doses up to 15 mg/kg/day in those aged <6 years, demonstrated acceptable safety and tolerability. For children weighing <30 kg, a dose increase of 40% (mg/kg dosing) is required to achieve comparable exposure with adults or children weighing ≥30 kg. These data will inform dose selection in phase 3 trials of the efficacy and safety of adjunctive pregabalin in children with refractory partial seizures.

[Concentrations of urine 6-sulfatoxymelatonin during the treatment of patients with epilepsy: a pilot clinical trial].

The effect of the epiphysis hormone melatonin on the brain bioelectrical activity is understudied: the data of experimental and clinical studies of melatonin effects are inconclusive and related mostly to exogenous administration. We studied 43 patients with focal epilepsy, 25 patients with cryptogenic epilepsy and 18 with symptomatic epilepsy. Carbamazepine and valproate were used as anticonvulsive drugs. Morning and evening urine concentrations of 6-sulfatoxymelatonin (6-COM), the main melatonin metabolite, were determined twice using immunoassay method: in autumn at the inclusion in the study and beginning of the anticonvulsant treatment and after 6 months, in spring, when anticonvulsant doses had been adjusted. The presence of epileptic seizures was associated with the reduction of melatonin concentration in the body that was supported by the decrease of urine 6-COM, in particular in the morning, in non-treated patients. Prescription of anticonvulsant treatment resulted in the increase of 6-COM. The concentration of the morning urine 6-COM was higher in patients with focal epilepsy receiving anticonvulsant treatment with valproate compared to those receiving carbamazepine: 49.28±6.71 and 37.09±5.43 ng/ml versus 20.00±3.6 and 13.11±2.08 ng/ml in patients treated with valproate and carbamazepine, respectively, before and after the adjustment.

Treatment with vigabatrin may mimic alpha-aminoadipic aciduria.

PURPOSE: We describe a secondary effect of treatment with vigabatrin (VGB). A significant increase in alpha-aminoadipic acid (AAA) occurred in plasma and urine of VGB-treated children, thus mimicking a known rare metabolic disease, alpha-aminoadipic aciduria (AAAuria). METHODS: We studied eight children, aged from 3 months to 5 years, who were receiving VGB for drug-resistant partial epilepsies. Plasma and urine amino acids were assayed with ninhydrin detection on an automated Beckman 6300 analyzer. RESULTS: In eight out of eight children, there was a significant increase of AAA in plasma and in urine. Plasma values ranged from 7 to 8 microM (control values, < 5) and urinary values from 67 to 274 mmol/mol creatinine (control values, < 25). CONCLUSIONS: The concentrations of AAA in these VGB-treated children were as high as the concentrations found in the inherited metabolic disease, AAAuria. This could lead to incorrect diagnosis and to inappropriate genetic counseling. Thus whenever a genetic metabolic disease is suspected, amino acid chromatography testing should be performed before initiation of treatment with VGB.

[Reactivity of the DOPA--dopamine--noradrenaline--adrenaline system in epileptics]. / Reaktivnost' sistemy DOFA--dofamin--noradrenalin--adrenalin u bol'nykh épilepsiei.

Epileptic patients were examined for the daily urine elimination of DOPA, dopamine (DA), noradrenaline (NA), and adrenaline (A). The changes in the excretion of these substances after L-DOPA intake and the adrenaline and insulin test were also investigated. In addition to the evidence about the preserved reactivity of the DOPA-DA-NA-A system to L-DOPA intake, data were obtained pointing to its strain and a reduction in the reserve potentialities. The use of the adrenaline test disclosed the absence of, or a negative response on the part of DA and A in half of the patients, which correlated with definite clinical parameters. In one third of the patients, the insulin test was not accompanied by any increase in the excretion of A or its precursors. The findings obtained are indicative of the insufficiency of homeostatic reactions in epileptics and, possibly, of the deficit of the repolarizing mechanisms.