Therapeutic Salivary Monitoring of Perampanel in Patients with Epilepsy Using a Volumetric Absorptive Microsampling Technique.

The objective of this study was to validate a novel assay using the volumetric absorptive microsampling (VAMS) technique combined with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the determination of the antiseizure medication perampanel in saliva and its clinical applicability in patients with epilepsy. VAMS tips were loaded with 30 μL of saliva and dried for 60 min. Analytes were extracted with methanol.

Melatonin versus Sleep Deprivation for Sleep Induction in Nap Electroencephalography: Protocol for a Prospective Randomized Crossover Trial in Children and Young Adults with Epilepsy.

Electroencephalography (EEG) continues to be a pivotal investigation in children with epilepsy, providing diagnostic evidence and supporting syndromic classification. In the pediatric population, electroencephalographic recordings are frequently performed during sleep, since this procedure reduces the number of artifacts and activates epileptiform abnormalities. To date, no shared guidelines are available for sleep induction in EEG.

On-Line Solid Phase Extraction High Performance Liquid Chromatography Method Coupled With Tandem Mass Spectrometry for the Therapeutic Monitoring of Cannabidiol and 7-Hydroxy-cannabidiol in Human Serum and Saliva.

Cannabidiol is a novel antiseizure medication approved in Europe and the US for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis complex. We describe in this article a new and simple liquid chromatography-mass spectrometry method (LC-MS/MS) for the determination of cannabidiol and its active metabolite 7-hydroxy-cannabidiol in microvolumes of serum and saliva (50 μl), to be used as a tool for therapeutic drug monitoring (TDM) and pharmacokinetic studies. After on-line solid phase extraction cannabidiol, 7-hydroxy-cannabidiol and the internal standard cannabidiol- are separated on a monolithic C18 column under gradient conditions.

Google Earth Engine as Multi-Sensor Open-Source Tool for Supporting the Preservation of Archaeological Areas: The Case Study of Flood and Fire Mapping in Metaponto, Italy.

In recent years, the impact of Climate change, anthropogenic and natural hazards (such as earthquakes, landslides, floods, tsunamis, fires) has dramatically increased and adversely affected modern and past human buildings including outstanding cultural properties and UNESCO heritage sites. Research about protection/monitoring of cultural heritage is crucial to preserve our cultural properties and (with them also) our history and identity. This paper is focused on the use of the open-source Google Earth Engine tool herein used to analyze flood and fire events which affected the area of Metaponto (southern Italy), near the homonymous Greek-Roman archaeological site.

Does screening for adverse effects improve health outcomes in epilepsy? A randomized trial.

Objective: To determine whether systematic screening for adverse effects of antiepileptic drugs (AEDs) reduces toxicity burden and improves health-related quality of life in patients with epilepsy.

Methods: Consecutive patients with uncontrolled seizures aged ≥16 years and a high Adverse Event Profile (AEP) score were randomized to 2 groups and followed up for 18 months at 11 referral centers. AEP scores were made available to treating physicians at all visits in the intervention group, but not in the control group.

Relationship between saliva and plasma rufinamide concentrations in patients with epilepsy.

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated.

Determination of Perampanel in Dried Plasma Spots: Applicability to Therapeutic Drug Monitoring.

Background: Although therapeutic drug monitoring of antiepileptic drugs is typically based on the analysis of plasma samples, alternative matrices, such as dried plasma spots (DPSs), may offer specific advantages. The aims of this work were to (1) develop and validate a bioanalytical method for the quantitative determination of the second-generation antiepileptic drug perampanel in DPSs; (2) assess short- and long-term stability of perampanel in DPSs; and (3) test the clinical applicability of the developed method.

Methods: Two hundred microliters of plasma were dispensed on a glass paper filter and dried.

A simple and rapid HPLC-UV method for the determination of retigabine in human plasma.

A simple and rapid high-performance liquid chromatographic method with ultraviolet detection was developed for the quantitative determination of retigabine, known also as ezogabine, in human plasma. The assay uses a simple solid-phase extraction for sample preparation and direct injection of the extract into the chromatograph. Flupirtine is used as an internal standard.

Development and Validation of an HPLC-UV Assay for the Therapeutic Monitoring of the New Antiepileptic Drug Perampanel in Human Plasma.

Background: Perampanel, a new specific non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist, has been recently approved in the United States and the European Union for the adjunctive treatment of focal seizures and primary generalized tonic-clonic seizures associated with idiopathic generalized epilepsy. A positive relationship between plasma perampanel concentration and improvement in seizure control has been identified in regulatory trials, suggesting that therapeutic drug monitoring could be useful in optimizing clinical response in patients with epilepsy treated with perampanel. The development of a simple and broadly applicable method for measuring plasma perampanel concentrations is desirable to permit the use of TDM for this drug in clinical practice.

Zonisamide in the management of epilepsy in the elderly.

Zonisamide (ZNS), a second-generation antiepileptic drug, indicated as add-on treatment of focal epilepsy, has been recently approved as monotherapy for the treatment of partial seizures in adults affected by newly diagnosed epilepsy in Europe. Evidence on the efficacy and tolerability of antiepileptic drugs in the elderly is still lacking as these patients are frequently excluded from clinical trials. Here, a comprehensive overview of available data regarding the use of ZNS in the treatment of epilepsy in elderly people is provided.

Comprehensive educational plan for patients with epilepsy and comorbidity (EDU-COM): a pragmatic randomised trial.

Background: The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined.

Objective: The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity.

Methods: 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care.

Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation.

Currently available epilepsy drugs only affect the symptoms (seizures), and there is a need for innovative treatments that target the underlying disease. Increasing evidence points to inflammation as a potentially important mechanism in epileptogenesis. In the last decade, a new generation of etiologically realistic syndrome-specific experimental models have been developed, which are expected to capture the epileptogenic mechanisms operating in corresponding patient populations, and to exhibit similar treatment responsiveness.

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.

Methods: Individuals with epilepsy whose seizures failed to respond to at least one AED were enrolled consecutively at 11 tertiary referral centers. HRQOL was assessed by the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), AEs by the Adverse Event Profile (AEP), and depressive symptoms by the Beck Depression Inventory-II (BDI-II).

Novel medications for epilepsy.

Despite the introduction of many second-generation antiepileptic drugs (AEDs) in the last 2 decades, the proportion of individuals with pharmacoresistant 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.

Development and validation of an HPLC-UV detection assay for the determination of rufinamide in human plasma and saliva.

The development of a simple and rapid high-performance liquid chromatography (HPLC) method for the determination of the new antiepileptic drug rufinamide (RFN) in human plasma and saliva is reported. Samples (250 μl) are alkalinized with ammonium hydroxide (pH 9.25) and extracted with dichloromethane using metoclopramide as internal standard.

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.

Methods: Patients were randomized in a 2:1 ratio to receive de novo monotherapy with levetiracetam (up to 30 mg/kg/day) or placebo for 2 weeks under double-blind conditions. Responder status (primary end point) was defined as freedom from clinical seizures on days 13 and 14 and from electroencephalographic (EEG) seizures during a standard EEG recording with hyperventilation and intermittent photic stimulation on day 14.

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.

Characteristics of a large population of patients with refractory epilepsy attending tertiary referral centers in Italy.

The characteristics of 1,124 consecutive adults and children with refractory epilepsy attending 11 tertiary referral centers in Italy were investigated at enrollment into a prospective observational study. Among 933 adults (age 16-86 years), the most common syndromes were symptomatic (43.7%) and cryptogenic (39.

A novel enantioselective microassay for the high-performance liquid chromatography determination of oxcarbazepine and its active metabolite monohydroxycarbazepine in human plasma.

A simple and innovative assay is described that allows the determination of the antiepileptic drug oxcarbazepine and the chiral separation of the two enantiomers of its active metabolite monohydroxycarbazepine (licarbazepine). The assay requires liquid-liquid extraction of the sample (200 microL) into tert-butyl methyl ether and dichloromethane, drying of the organic phase under a nitrogen stream, reconstitution with the mobile phase, and injection in the high-performance liquid chromatography system after filtering. Separation of oxcarbazepine, R-(-)-monohydroxycarbazepine, S-(+)-monohydroxycarbazepine, and the second-step metabolite 10,11-trans-dihydroxycarbamazepine (racemate) is achieved with a Chiralcel ODR column and potassium hexafluorophosphate/acetonitrile as mobile phase.

Stereoselective determination of vigabatrin enantiomers in human plasma by high performance liquid chromatography using UV detection.

A rapid and simple high-performance liquid chromatographic method for the determination of the R-(-)- and S-(+)-enantiomers of the antiepileptic drug vigabatrin in human plasma is described. After adding the internal standard (1-aminomethyl-cycloheptyl-acetic acid), plasma samples (200 microL) are deproteinized with acetonitrile and the supernatant is derivatized with 2,4,6 trinitrobenzene sulfonic acid (TNBSA). Separation is achieved on a reversed-phase cellulose-based chiral column (Chiralcel-ODR, 250 mm x 4.

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

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.

Methods: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay.

The influence of old age and enzyme inducing comedication on the pharmacokinetics of valproic acid at steady-state: A case-matched evaluation based on therapeutic drug monitoring data.

Purpose: To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication.

Methods: The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged > or = 65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/F) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20-50 years and matched for gender, body weight and antiepileptic drug (AED) comedication.

Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine.

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.

Methods: Twelve healthy subjects received a single oral dose of TPM (200 mg) on two randomized occasions. On one occasion, TPM was administered alone, and on the other, it was given on day 18 of a 24-day treatment with CBZ (maintenance dosage, 600 mg/day).

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.