Search

A prospective multicenter observational study was undertaken on children and adults with epilepsy in whom first monotherapy failed, to assess indications and effects of alternative monotherapy vs. polytherapy. Patients were followed until 12-month remission, drug withdrawal, or up to 18months. Monotherapy and polytherapy were compared for patients' baseline features, indication, retention time, remission, adverse events (AE), quality of life, and direct and indirect costs. Included were 157 men and 174 women, aged 2-86years. Of the patients, 72.2% were switched to alternative monotherapy. Baseline treatment was changed for lack of efficacy (73.9%) or adverse events (26.1%). Two hundred forty-three completed the study (remission: 175; 72.0%). Retention time, hospital admissions, days off-work and off-school, and quality of life did not differ between the two treatment groups. Patients were followed for 365.3person-years. Three hundred eighty-three incident AEs were reported by 46.4% of patients in monotherapy and 40.2% in polytherapy (serious AEs: 9.6% vs. 8.7%, mostly nondrug-related).

Our work aimed to provide a topographical analysis of all known ionotropic P2X(1-7) and metabotropic P2Y(1,2,4,6,11-14) receptors that are present in vivo at the protein level in the basal ganglia nuclei and particularly in rat brain slices from striatum and substantia nigra. By immunohistochemistry-confocal and Western blotting techniques, we show that, with the exception of P2Y(11,13) receptors, all other subtypes are specifically expressed in these areas in different amounts, with ratings of low (P2X(5,6) and P2Y(1,6,14) in striatum), medium (P2X(3) in striatum and substantia nigra, P2X(6,7) and P2Y(1) in substantia nigra) and high. Moreover, we describe that P2 receptors are localized on neurons (colocalizing with neurofilament light, medium and heavy chains) with features that are either dopaminergic (colocalizing with tyrosine hydroxylase) or GABAergic (colocalizing with parvalbumin and calbindin), and they are also present on astrocytes (P2Y(2,4), colocalizing with glial fibrillary acidic protein). In addition, we aimed to investigate the expression of P2 receptors after dopamine denervation, obtained by using unilateral injection of 6-hydroxydopamine as an animal model of Parkinson's disease. This generates a rearrangement of P2 proteins: most P2X and P2Y receptors are decreased on GABAergic and dopaminergic neurons, in the lesioned striatum and substantia nigra, respectively, as a consequence of dopaminergic denervation and/or neuronal degeneration. Conversely, P2X(1,3,4,6) on GABAergic neurons and P2Y(4) on astrocytes augment their expression exclusively in the lesioned substantia nigra reticulata, probably as a compensatory reaction to dopamine shortage. These results disclose the presence of P2 receptors in the normal and lesioned nigro-striatal circuit, and suggest their potential participation in the mechanisms of Parkinson's disease.

Idiopathic Epilepsy (IE) in the dog is the major cause of epileptic seizures. Neoplasia, inflammatory/infectious diseases, cerebrovascular accidents are the most common causes of structural epilepsy. Hypoglycemia, Hypocalcemia and Hepatic Encephalopathy are the most common causes of reactive seizures. IE treatment is symptomatic. The goal of the therapy is the reduction of severity and frequency of seizures. The most important guideline includes the balance between a good control of seizures activity and development of relevant side effects. Phenobarbital and Bromide are still the two drugs most commonly used in the IE treatment. Among the new generation drugs, Zonisamide and Levetiracetam are the best known and most commonly used in veterinary medicine. Imepitoin is a new drug, recently and specifically developed for dogs, aimed to replace phenobarbital in the treatment of IE.

The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years. In view of the importance of the issue, the Italian League against Epilepsy (LICE) set up an ad hoc working group whose task was to assess available evidence on the efficacy and safety of generic AEDs in the treatment of epilepsy and to produce recommendations on their use. A careful review of the literature revealed no adequately powered randomized controlled trials that assessed the risk/benefit ratio of generic substitution. Although there have been reports of loss or worsened seizure control, or appearance of adverse events, following the switch from brand products to generics, a critical assessment of the evidence generally does not allow us to establish a cause-effect relationship between the switch and a change in clinical status. Overall, the working group concluded that generic AEDs meeting current regulatory criteria for bioequivalence represent a valuable choice in the management of epilepsy by allowing a substantial reduction of treatment costs, particularly in patients initiating monotherapy or adjunctive treatment and in those with persistent seizures. The working group considered that in patients who achieved seizure freedom a modest change in plasma drug levels, which may occasionally occur even after substitution of products that meet bioequivalence criteria, could in rare cases lead to seizure breakthrough. Therefore, generic substitution is not recommended in patients who achieved seizure remission. Switches between a particular generic and another generic should also be preferably avoided. Finally, sustained-release AED formulations should not be used interchangeably with immediate-release brand or generic products. Patients need to be informed about the stringent criteria that currently govern the approval of generic products and about the implications of the use of generic AEDs, and their opinion should be taken into consideration at the time of prescribing.

The antiepileptic drug Levetiracetam (Lev) has neuroprotective properties in experimental stroke, cerebral hemorrhage and neurotrauma. In these conditions, non-convulsive seizures (NCSs) propagate from the core of the focal lesion into perilesional tissue, enlarging the damaged area and promoting epileptogenesis. Here, we explore whether Lev neuroprotective effect is accompanied by changes in NCS generation or propagation. In particular, we performed continuous EEG recordings before and after the permanent occlusion of the middle cerebral artery (pMCAO) in rats that received Lev (100 mg/kg) or its vehicle immediately before surgery. Both in Lev-treated and in control rats, EEG activity was suppressed after pMCAO. In control but not in Lev-treated rats, EEG activity reappeared approximately 30-45 min after pMCAO. It initially consisted in single spikes and, then, evolved into spike-and-wave and polyspike-and-wave discharges. In Lev-treated rats, only rare spike events were observed and the EEG power was significantly smaller than in controls. Approximately 24 hours after pMCAO, EEG activity increased in Lev-treated rats because of the appearance of polyspike events whose power was, however, significantly smaller than in controls. In rats sacrificed 24 hours after pMCAO, the ischemic lesion was approximately 50% smaller in Lev-treated than in control rats. A similar neuroprotection was observed in rats sacrificed 72 hours after pMCAO. In conclusion, in rats subjected to pMCAO, a single Lev injection suppresses NCS occurrence for at least 24 hours. This electrophysiological effect could explain the long lasting reduction of ischemic brain damage caused by this drug.

We present an implementation of a method we previously reported allowing the newer antiepileptic drugs (AEDs) rufinamide (RFN) and zonisamide (ZNS) to be simultaneously determined with lamotrigine (LTG), oxcarbazepine's (OXC) main active metabolite monohydroxycarbamazepine (MHD) and felbamate (FBM) in plasma of patients with epilepsy using high performance liquid chromatography (HPLC) with UV detection. Plasma samples (250 microL) were deproteinized by 1 mL acetonitrile spiked with citalopram as internal standard (I.S.). HPLC analysis was carried out on a Synergi 4 microm Hydro-RP, 250 mm x 4.6 mm I.D. column. The mobile phase was a mixture of potassium dihydrogen phosphate buffer (50 mM, pH 4.5), acetonitrile and methanol (65:26.2:8.8, v/v/v) at an isocratic flow rate of 0.8 mL/min. The UV detector was set at 210 nm. The chromatographic run lasted 19 min. Commonly coprescribed AEDs did not interfere with the assay. Calibration curves were linear for both AEDs over a range of 2-40 microg/mL for RFN and 2-80 microg/mL for ZNS. The limit of quantitation was 2 microg/mL for both analytes and the absolute recovery ranged from 97% to 103% for RFN, ZNS and the I.S. Intra- and interassay precision and accuracy were lower than 10% at all tested concentrations. The present study describes the first simple and validated method for RFN determination in plasma of patients with epilepsy. By grouping different new AEDs in the same assay the method can be advantageous for therapeutic drug monitoring (TDM).

Il monitoraggio terapeutico dei farmaci (TDM) antiepilettici costituisce oggi un affermato supporto alla terapia medica delle epilessie. La terapia dell’epilessia si presta particolarmente all’applicazione del TDM, sia per il decorso variabile ed insidioso della patologia (le crisi avvengono ad intervalli irregolari e non prevedibili; sintomi clinici e segni di tossicità possono essere difficili da valutare), sia per le caratteristiche dei farmaci utilizzati, dotati spesso di un basso indice terapeutico, con una cinetica interindividuale molto variabile, ed un alto potenziale d’interazione farmacologiche. In questa rassegna sono descritti il razionale e le procedure per la corretta esecuzione ed interpretazione del monitoraggio dei farmaci antiepilettici, nella prospettiva di una gestione individualizzata della terapia della epilessia nel singolo paziente. Negli ultimi 10-15 anni sono stati commercializzati in Italia numerosi nuovi farmaci antiepilettici (vigabatrin, lamotrigina, gabapentin, felbamato, oxcarbazepina, tiagabina, topiramato, levetiracetam, pregabalin e zonisamide). Proposti dalle case farmaceutiche produttrici come farmaci più facili da gestire, per le migliori caratteristiche farmacocinetiche e il più basso potenziale di interazione, è stato suggerito che il loro utilizzo non richieda l’ausilio del monitoraggio delle concentrazioni, con vantaggi in termini di minori costi aggiunti e di semplificazione nella gestione dei pazienti. Tuttavia nella fase di post-commercializzazione sono emerse per diversi dei nuovi farmaci antiepilettici evidenze che indicano una variabilità cinetica ed un potenziale di interazione comparabili a quelli dei vecchi farmaci e che rendono plausibile sul piano teorico e su quello pratico l’applicazione del TDM anche a molti di questi prodotti.

Gabapentin (acido 2-[1-(amminometil)cicloesil]acetico) e vigabatrin (acido 4-ammino-5-esenoico) sono due farmaci antiepilettici a struttura aminoacidica. Mentre il preciso meccanismo d'azione del gabapentin è ancora ignoto, si ritiene che il vigabatrin agisca inibendo la GABA transaminasi, con effetti inbitori sulla trasmissione neuronale. Come per molti altri antiepilettici, anche per gabapentin e vigabatrin è necessario personalizzare la terapia, effettuando un accurato monitoraggio terapeutico dei pazienti. È stato quindi sviluppato un metodo, basato sulla cromatografia liquida, per l’analisi simultanea di questi due farmaci in plasma umano. A tale scopo si è utilizzata una colonna a fase inversa C8 ed una fase mobile composta da tampone fosfato acido ed acetonitrile. Poiché le molecole non presentano cromofori significativi, la rivelazione spettrofotometrica non è direttamente applicabile. Pertanto, si è deciso di accoppiare all'HPLC una rivelazione spettrofluorimetrica dopo derivatizzazione degli analiti con dansil cloruro (eccitazione = 318 nm, emissione = 510 nm). Prima della derivatizzazione, i campioni biologici vengono purificati mediante estrazione in fase solida (SPE) con cartucce MCX (modalità mista: fase inversa – scambio cationico). Il metodo è ora in fase di convalida, ma i risultati preliminari sono promettenti: le rese d'estrazione sono maggiori di 80% e si è ottenuta una buona linearità nei range attesi di concentrazioni plasmatiche dei farmaci.

Epilepsy is a common clinical problem in patients with brain tumours, strongly affecting patients' quality of life. Tumour-related seizures are often difficult to control, and the clinical picture is complicated by frequent interactions between antiepileptic drugs (AEDs) and antineoplastic agents. We studied the safety and efficacy of levetiracetam (LEV), a new AED with a different pharmacological profile from traditional anticonvulsants, in 19 patients (6 females; age range 28-70 years, mean 48 years) with supratentorial gliomas and epilepsy. Seizure types were simple partial in four patients, complex partial in 4, complex partial with secondary generalization in 7, and generalized tonic-clonic in 4. LEV was added to the existing AED treatment on account of persisting seizures, and titrated at dosages of 1,000-3,000 mg/day. Patients were seen at the Outpatient's Centre every 1-3 months, and followed-up for 7-50 months (mean 25 months, median 20 months). At the end of the observation period, nine patients were seizure free (seizure free period ranging from 7 to 33 months, mean 16, median 12) and five patients reported an improvement in seizure-frequency from daily to weekly (n=1) or from weekly to monthly (n=3). Seizure frequency was unmodified in four patients and increased (from monthly to weekly) in one. No LEV-related adverse effects were observed. LEV plasma concentrations monitored in 12 subjects ranged from 11.9 to 82.1 microg/ml. Our preliminary open data indicate that add-on treatment with LEV in patients with brain tumours is safe and appears to be effective in reducing seizure frequency. Controlled studies on larger populations are warranted to confirm these open observations.