Cinzia Fattore

Determinants of health-related quality of life in pharmacoresistant epilepsy: Results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments

Purpose:  To evaluate the relative contribution of demographic and epilepsy‐related variables, depressive symptoms, and adverse effects (AEs) of antiepileptic drugs (AEDs) to health‐related quality of life (HRQOL) in adults with pharmacoresistant epilepsy.

Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

Summary: Purpose: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives.

A Multicenter Randomized Controlled Trial on the Clinical Impact of Therapeutic Drug Monitoring in Patients with Newly Diagnosed Epilepsy

Summary: Purpose: To assess the clinical impact of monitoring serum concentrations of antiepileptic drugs (AEDs) in patients with newly diagnosed epilepsy.

Pharmacokinetic and Metabolic Investigation of Topiramate Disposition in Healthy Subjects in the Absence and in the Presence of Enzyme Induction by Carbamazepine

Summary:  Purpose: To characterize the metabolic profile of topiramate (TPM) in humans and to assess the influence of enzyme induction by carbamazepine (CBZ) on the pharmacokinetics and metabolic profile of TPM.

Novel Medications for Epilepsy

Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the last 2 decades, the proportion of individuals with pharmaco-resistant epilepsy has not been reduced substantially compared with the late 1960s. All currently available AEDs also have limitations in terms of adverse effects and susceptibility to be involved in clinically important drug-drug interactions. Therefore, the search for potentially more effective and better tolerated agents is continuing. This article reviews the pharmacological and clinical profile of the latest compounds to receive marketing authorization.Since the beginning of 2008, three novel AEDs, lacosamide, eslicarbazepine acetate and retigabine (also known as ezogabine), have become commercially available in Europe, with lacosamide and retigabine also being licensed in the US. All three agents are indicated for the adjunctive treatment of focal seizures in adults.Eslicarbazepine acetate is a produg for eslicarbazepine, which acts by blocking voltage-dependent sodium channels. Lacosamide enhances the slow inactivation phase of voltage-dependent sodium channels, and retigabine potentiates neuronal M-currents by opening Kv 7.2–7.5 potassium channels.All three agents, which are well absorbed from the gastrointestinal tract, exhibit linear pharmacokinetics. Lacosamide is also available as an intravenous formulation intended as replacement therapy for patients temporarily unable to take oral medications. All three drugs are eliminated partly unchanged in urine and partly by biotransformation through glucuronide conjugation (eslicarbazepine, retigabine), N-acetylation (retigabine) and oxidative demethylation (lacosamide). The half-life is in the order of 8–20 hours for eslicarbazepine, 12–16 hours for lacosamide and 6–10 hours for retigabine. Based on the limited information available to date, the ability of these agents to cause pharmacokinetic drug interactions appears to be relatively modest, although eslicarbazepine can cause a significant decrease in the blood levels of ethinylestradiol, levonorgestrel and simvastatin.The approved effective dose ranges are 200–400 mg/day in two divided doses for lacosamide, 800–1200 mg/day once daily for eslicarbazepine acetate, and 600–1200 mg/day in three divided doses for retigabine. In phase III, randomized, double-blind, adjunctive therapy trials, responder rates (proportion of patients with ≥50% reduction in seizure frequency vs baseline) at the highest approved dose were comparable for the three drugs (eslicarbazepine acetate: 37–43% vs 13–20% for placebo; lacosamide: 38–41% vs 18–26% for placebo; retigabine: 33–44% vs 16–18% for placebo). The adverse events most commonly reported with active treatment compared with placebo included dizziness, diplopia and nausea for lacosamide; dizziness, somnolence and nausea for eslicarbazepine acetate; and dizziness, somnolence and fatigue for retigabine.The role of these agents in the treatment algorithm will be increasingly defined as clinical experience accumulates. At present, their use is largely restricted to the adjunctive treatment of focal seizures, with or without secondary generalization, in adults with epilepsy who failed to achieve seizure freedom after having tried two or more first-line agents.

Increased apparent oral clearance of valproic acid during intake of combined contraceptive steroids in women with epilepsy.

Summary:  Purpose: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steady‐state during a cycle of intake of combined hormonal contraceptive (HC) steroids.

Improved enantioselective assay for the determination of fluoxetine and norfluoxetine enantiomers in human plasma by liquid chromatography.

A simple and innovative assay is described which allows the chiral separation of the four enantiomers of fluoxetine and norfluoxetine, with performance characteristics adequate for therapeutic drug monitoring. The assay requires liquid-liquid extraction into acetonitrile/n-hexane/isopropylic alcohol and re-extraction into phosphoric acid for clean-up. The acidic layer is injected onto the HPLC system after filtering. Separation of the analytes is achieved with a Chiralcel ODR column and a mobile phase consisting of potassium hexafluorophosphate/acetonitrile. Detection is made by ultraviolet absorbance at 227 nm. Standard curves are linear for each enantiomer (r(2)>/=0.992) over the range of 10-1000 ng/ml with a limit of quantification of 10 ng/ml for each enantiomer. Within-day and between-day CV% are </=10% for each enantiomer.

A double-blind, placebo-controlled study on the effect of vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral contraceptives in healthy female volunteers

Summary: Purpose: This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects.

Patterns of prescription of antiepileptic drugs in patients with refractory epilepsy at tertiary referral centres in Italy

PURPOSE To evaluate the pattern of prescription of antiepileptic drugs (AEDs) and other medications in a representative population of patients with refractory epilepsy attending tertiary referral centres in Italy. METHODS Descriptive analysis of data obtained at baseline from 933 adults and 191 children with refractory epilepsy enrolled consecutively in an observational study at 11 tertiary referral centres in Italy. Multivariate logistic regression analysis was used to assess predictors of utilization of the most commonly prescribed AEDs. RESULTS Polytherapy was used in 79% of adults and 75% of children, with over one-third of adults and children being prescribed ≥3 AEDs. In adults, the most commonly used AEDs were levetiracetam (35%), carbamazepine (34%) and lamotrigine (30%). In children, valproic acid was by far the most commonly used AED (46%), followed by carbamazepine (27%), topiramate (21%), and phenobarbital (20%). The most common AED in partial epilepsy was carbamazepine (331 out of 893 patients, 37%), followed by levetiracetam (33%) and lamotrigine (26%). In generalized or undetermined epilepsies, the AEDs most commonly used were valproic acid (139 out of 223 patients, 62%), lamotrigine (33%) and levetiracetam (28%). Second generation AEDs were prescribed in 81% of adults and 54% of children. Comedications used for indications other than epilepsy were used by 32% of adults and 17% of children. CONCLUSIONS Prescription patterns were consistent with current evidence about the spectrum of efficacy of individual AEDs in different epilepsy syndromes. The high prevalence of polytherapy, including combinations of three or more AEDs, is a cause for concern.

A multicenter, randomized, placebo-controlled trial of levetiracetam in children and adolescents with newly diagnosed absence epilepsy

Purpose:  To evaluate the potential efficacy of levetiracetam as an antiabsence agent in children and adolescents with newly diagnosed childhood or juvenile absence epilepsy.