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Biomedical subjects

E Perucca

Publications and source records attributed to E Perucca.

At least 19 recordsLinked to original sources
PubMed2005

Pharmacological and clinical aspects of antiepileptic drug use in the elderly.

In this article, epidemiological and clinical aspects related to the use of antiepileptic drugs (AEDs) in the elderly are highlighted. Studies have shown that people with epilepsy receiving AED treatment show important deficits in physical and social functioning compared with age-matched people without epilepsy. To what extent these deficits can be ascribed to epilepsy per se or to the consequences of AED treatment remains to be clarified. The importance of characterizing the effects of AEDs in an elderly population is highlighted by epidemiological surveys indicating that the prevalence of AED use is increased in elderly people, particularly in those living in nursing homes. Both the pharmacokinetics and the pharmacodynamics of AEDs may be altered in old age, which may contribute to the observation that AEDs are among the drug classes most commonly implicated as causing adverse drug reactions in an aged population. Age alone is one of several contributors to alterations in AED response in the elderly; other factors include physical frailty, co-morbidities, dietary influences, and drug interactions. Individualization of dosage, avoidance of unnecessary polypharmacy, and careful observation of clinical response are essential for an effective and safe utilization of AEDs in an elderly population.

Aged↗
PubMed2005

Adverse effects of antiepileptic drugs.

Adverse effects of antiepileptic drugs (AEDs) are common, can have a considerable impact on quality of life and contribute to treatment failure in up to 40% of patients. The adverse effect profiles of AEDs differ greatly and are often a determining factor in drug selection because of the similar efficacy rates shown by most AEDs. The most common adverse effects are dose dependent and reversible. Cognitive impairment is of particular concern, especially for patients who work or study. Idiosyncratic effects, such as skin rashes, and chronic effects, such as weight gain, can lead to high rates of treatment discontinuation and complicate clinical management. Nearly all conventional AEDs increase the risk of congenital malformations when taken during pregnancy, with valproate posing a potentially greater risk, whereas the potential teratogenicity of new generation AEDs is largely unknown. Most conventional AEDs have a poor record when it comes to drug interactions, largely because of their tendency to interfere with hepatic drug metabolism. Some newer AEDs have no effect on hepatic drug metabolizing enzymes and are renally excreted, resulting in a lower potential for drug interactions. However, further research is needed to confirm the apparent improvement in tolerability offered by some of the newer AEDs.

Abnormalities, Drug-Induced↗
PubMed2003

Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials.

PURPOSE: To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state. METHODS: Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000-4000 mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose). RESULTS: Estimated pharmacokinetic values, normalized to a dose of 1 mgkg(-1) b.i.d., were: concentration at 1h (C(1h)) 2.1 microgram ml(-1), concentration at 12h (C(12h)) 0.8 microgram ml(-1), area under the curve from 0 to 12h (AUC(0-12h)) 17.1 microgram ml(-1)h, half-life (t(1/2)) 8.1h, and apparent oral clearance (CL/F) 0.97 mlmin(-1)kg(-1). Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t(1/2) tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest. CONCLUSIONS: Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.

Adult↗
PubMed2003

Epilepsy and comorbidity: infections and antimicrobials usage in relation to epilepsy management.

Infections are probably the most common preventable cause of epilepsy worldwide. There are concerns that endemic infections and infestations, such as malaria and neurocysticercosis, could be responsible for the increased incidence of epilepsy in the developing world. Cases of epilepsy associated with neurocysticercosis are also being seen increasingly in developed countries due to migration from, and travel to, endemic areas. When prescribing antimicrobial agents in patients with epilepsy a number of issues need to be considered, such as potential adverse effects on seizure control and interactions with concomitant antiepileptic drugs (AEDs). Some antimicrobial agents, including penicillins, cephalosporins, carbapenems, quinolones and antimalarials, can have proconvulsant activity and may precipitate seizures, even in patients who do not have epilepsy. Moreover, many antimicrobials increase or decrease the plasma levels of AEDs, whereas some AEDs may adversely affect the efficacy of antimicrobials.

Anti-Bacterial Agents↗
PubMed2002

Progress report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT VI).

The Sixth Eilat Conference on New Antiepileptic Drugs (AEDs) took place in Taormina, Sicily, Italy from 7th to 11th April, 2002. Basic scientists, clinical pharmacologists and neurologists from 27 countries attended the conference, whose main themes included dose-response relationships with conventional and recent AEDs, teratogenic effects of conventional and recent AEDs, update on clinical implications of AED metabolism, prevention of epileptogesis, and seizure aggravation by AEDs. According to tradition, the central part of the conference was devoted to a review of AEDs in development, as well to updates on AEDs, which have been marketed in recent years. This article summarizes the information presented on drugs in preclinical and clinical development, including carabersat (SB-204269), CGX-1007 (Conantokin-G), pregabalin, retigabine (D-23129), safinamide, SPD421 (DP-VPA), SPM 927, talampanel and valrocemide (TV 1901). Updates on fosphenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, new formulations of valproic acid, and the antiepileptic vagal stimulator device are also presented.

Animals↗
PubMed2001

Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia.

RATIONALE: Evaluation of relationships between serum antipsychotic drug concentrations and clinical response may provide valuable information for rational dosage adjustments. For risperidone, this relationship has been little investigated to date. OBJECTIVE: To assess the relationship between plasma concentrations of risperidone and its active 9-hydroxy-metabolite (9-OH-risperidone) and clinical response in schizophrenic patients who experienced an acute exacerbation of the disorder. METHODS: Forty-two patients (30 males, 12 females, age 24-60 years) were given risperidone at dosages ranging from 4 to 9 mg/day for 6 weeks. The design of the study was open and risperidone dosage could be adjusted individually according to clinical response. Steady-state plasma concentrations of risperidone and its 9-hydroxymetabolite were measured after 4 and 6 weeks using a specific HPLC assay. Psychopathological state was assessed at baseline and at weeks 2, 4, and 6 by means of the positive and negative syndrome scale (PANSS), and patients were considered responders if they showed a greater than 20% reduction in total PANSS score at final evaluation compared with baseline. RESULTS: Mean plasma concentrations of risperidone, 9-OH-risperidone, and active moiety (sum of risperidone and 9-OH-risperidone concentrations) did not differ between responders (n = 28) and non-responders (n = 14). No correlation between plasma levels and percent decrease in total PANSS score was found for risperidone (rs = -0.187, NS), 9-OH-risperidone (rs = 0.246, NS), and active moiety (rs = 0.249, NS). Active moiety concentrations in plasma were higher (P < 0.001) in patients developing clinically significant parkinsonian symptoms (n = 7) than in those with minimal (n = 7) or no drug-induced parkinsonism (n = 28). CONCLUSIONS: In chronic schizophrenic patients experiencing an acute exacerbation of the disorder, plasma levels of risperidone and its active metabolite correlate with the occurrence of parkinsonian side effects, whereas no significant correlation appears to exist with the degree of clinical improvement.

Adolescent↗
PubMed2001

Progress report on new antiepileptic drugs: a summary of the Fifth Eilat Conference (EILAT V).

The Fifth Eilat Conference on New Antiepileptic Drugs (AEDs) took place at the Dan Hotel, Eilat, Israel, 25-29 June 2000. Basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included recognition of unexpected adverse effects, new indications of AEDs, and patient-tailored AED therapy. According to tradition, the central part of the conference was devoted to a review of AEDs in development, as well to updates on AEDs that have been marketed in recent years. This article summarizes the information presented on drugs in preclinical and clinical development, including AWD 131-138, DP-valproate, harkoseride, LY300164, NPS 1776, NW 1015, pregabalin, remacemide, retigabine, rufinamide and valrocemide. The potential value of an innovative strategy, porcine embryonic GABAergic cell transplants, is also discussed. Finally, updates on felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide, and the antiepileptic vagal stimulator device are presented.

Animals↗
PubMed2001

Trial duration and follow-up.

The chronic nature of most seizure disorders requires that antiepileptic drugs (AEDs) be administered for many years. Therefore, new drugs should be evaluated over a period sufficient to assess potential development of tolerance as well as long-term safety. While patients and prescribers desire extensive long-term data prior to registration, too stringent requirements would discourage industry's investment into new treatments, and a compromise between these stakes should be sought. In add-on studies, it is recommended that patients completing double-blind assessment be offered indefinite open-label treatment, and that safety data be collected prospectively. Monotherapy trials in refractory patients include presurgical and conversion to monotherapy studies. Duration of assessment in these studies rarely exceeds few weeks, and endpoints relate to seizure deterioration rather than improvement; this surrogate measure of efficacy is not necessarily predictive of clinical usefulness and, in view of ethical concerns, the rationale for these studies should be questioned. There may be scope, however, for alternative study designs whereby refractory patients are converted to monotherapy and followed up for several months. Active-control long-term monotherapy trials in newly diagnosed patients represent the mainstay for evaluating efficacy and safety. In patients with partial or generalized tonic-clonic seizures, most trials conducted to date had a duration of 6-12 months, but this period may be insufficient to assess seizure freedom rates at optimized dosages, and at least one 2-year trial would be desirable. With respect to open-label follow-up, many protocols require that the randomization code not be broken until the database has been sealed. Patients completing blind assessment are often forced through unblinding procedures which involve tapering of trial medication and institution of an open-label therapy which may differ, in dosage or type of medication, from that taken previously. In view of ethical concerns, the rationale for this practice should also be questioned.

Anticonvulsants↗
PubMed2001

Trials in the elderly.

Epilepsy in the elderly differs from that in younger people in several respects. The incidence of seizures increases sharply with age and the seizures are more often symptomatic of underlying brain disease. The handling of antiepileptic drugs (AEDs) may be impaired by diminishing hepatic and renal function as age advances, and the pharmacodynamic response to drug therapy may be altered. In consequence, the elderly are more likely to experience adverse drug effects. Whether their seizures respond to drug treatment in a different way from younger patients is uncertain, but there are, nevertheless, convincing arguments for clinical trials being undertaken specifically in this population during the Phase II/IV development programme.

Aged↗
PubMed2001

Recent advances in the diagnosis and treatment of epilepsy.

Recent advances in the diagnosis and treatment of epilepsies are discussed with special consideration of epidemiology and classification, progress in neuroimaging, electrophysiological studies using EEG and MEG, initiation of medical and surgical treatment, the role of new antiepileptic drugs and selected aspects of genetics of idiopathic epilepsies. In addition from conclusions obtained by the review of recent developments suggestions for future work in Europe are discussed. A constructive approach from multicenter studies requires homologous definitions, documentations and standardization of procedures of trials for European multicenter studies.

Anticonvulsants↗
PubMed2001

Clinical pharmacology and therapeutic use of the new antiepileptic drugs.

Although older generation antiepileptic drugs (AEDs) such as carbamazepine, phenytoin and valproic acid continue to be widely used in the treatment of epilepsy, these drugs have important shortcomings such as a highly variable and nonlinear pharmacokinetics, a narrow therapeutic index, suboptimal response rates, and a propensity to cause significant adverse effects and drug interactions. In an attempt to overcome these problems, a new generation of AEDs has been introduced in the last decade. Compared with older agents, some of these drugs offer appreciable advantages in terms of less variable kinetics and, particularly in the case of gabapentin, levetiracetam and vigabatrin, a lower interaction potential. Lamotrigine, topiramate, zonisamide and felbamate protect against partial seizures and a variety of generalized seizure types, vigabatrin is effective against partial seizures (with or without secondary generalization) and infantile spasms, while the use of oxcarbazepine, tiagabine and gabapentin is mainly restricted to patients with partial epilepsy (and, in the case of oxcarbazepine, also primarily generalized tonic-clonic seizures). Levetiracetam, the latest AED to be introduced, has been found to be effective in partial seizures, but its potentially broader efficacy spectrum remains to be determined in clinical studies. Currently, the main use of new generation AEDs is in the adjunctive therapy of patients refractory to older agents. However, due to advantages in terms of tolerability and ease of use, some of these drugs are increasingly used for first-line management in certain subgroups of patients. Due to serious toxicity risks, felbamate and vigabatrin should be prescribed only in patients refractory to other drugs. In the case of vigabatrin, however, first line use may be justified in infants with spasms.

Anticonvulsants↗
PubMed2001

The management of refractory idiopathic epilepsies.

Idiopathic epilepsies comprise a wide variety of partial and generalized syndromes that have in common a known or presumed genetic etiology and the lack of overt abnormalities other than the epilepsy itself. Most of these epilepsies have a benign natural history and/or show a favorable response to antiepileptic drug (AED) therapy, but pharmacoresistance does occur in some patients. In general, therapeutic algorithms in idiopathic partial epilepsies (IPEs) are similar to those used for symptomatic partial epilepsies, but aggressive pharmacologic therapy is rarely indicated in these patients. In self-limited conditions such as benign epilepsy of childhood with centrotemporal spikes or some forms of benign epilepsy with occipital paroxysms, AED treatment may not even be indicated unless seizures interfere significantly with quality of life. Valproate (VPA) is usually regarded as the drug of choice in idiopathic generalized epilepsies (IGEs). Most patients become rapidly seizure free, and poor compliance or prescription of an inappropriate AED because of misdiagnosis are the most common causes of treatment failure in IGEs. In those patients who did not respond well to VPA (or in whom VPA is considered contraindicated), the choice of alternative AEDs is guided by syndromic diagnosis and associated possible coexistence of multiple seizure types. Lamotrigine is establishing itself as a useful agent for many refractory IGEs, and might be considered for first-line use in selected patients. Topiramate (TPM) is another promising new agent in the management of refractory tonic-clonic seizures of nonfocal onset, but its potential efficacy against other primarily generalized seizure types has not been clearly established. Some of the older drugs, particularly ethosuximide (ESM), barbiturates, and benzodiazepines (BZDs), still have an important role in the management of refractory IGEs, especially in combination with VPA. Because carbamazepine (CBZ), phenytoin (PHT), tiagabine (TGB), vigabatrin (VGB), and gabapentin (GBP) may precipitate or aggravate absence and/or myoclonic jerks, their role in IGE syndromes associated with multiple seizure types is limited mostly to adjunctive use in patients unresponsive to first-line therapy.

Adolescent↗
PubMed2001

Tiagabine in clinical practice.

Among the newly introduced antiepileptic drugs (AEDs), tiagabine (TGB) stands out as a compound with a well-understood and documented mechanism of action. It is a lipophilic derivative of nipecotic acid that blocks gamma-aminobutyric acid (GABA) reuptake by inhibition of the GAT-1 transportation system, and that has no other significant pharmacodynamic effect. The relationship between intake and blood levels is linear. Usual daily maintenance doses range from 20 to 50 mg. It is completely absorbed by the gastrointestinal tract, and its half-life is approximately 7-9 h. TGB is sensitive to enzyme induction: when coprescribed with enzyme-inducing AEDs, its half-life is shortened to 2-3 h, whereas the daily dosage has to be increased into the upper range. It should be given 3 times per day. Placebo-controlled, double-blind, add-on studies conducted in patients with drug-resistant focal epilepsies have demonstrated its efficacy and overall safety. The clinical benefits appear to persist over time. Data on its use in monotherapy are scanty. The efficacy and tolerability of TGB in the pediatric age still remain to be investigated adequately. In daily practice, TGB appears to be a safe drug, but mild to moderate side effects are frequently seen, especially during titration: these include dizziness and fatigue, and are clearly abated when the drug is absorbed during meals. Titration should be especially slow, no faster than 5 mg weekly. Clinicians also should beware of the possible occurrence of confusion, which may be misdiagnosed as absence status, a short-lasting, quickly reversible central nervous system-related side effect that appears to be correlated with the peak plasma concentrations of TGB. Particularly beneficial indications for TGB and/or AED associations including TGB have not been pointed out, but there is a hint that it works best in temporal lobe epilepsies.

Anticonvulsants↗
PubMed2001

Single-dose pharmacokinetics of lamotrigine in children: influence of age and antiepileptic comedication.

To evaluate the influence of pediatric age and antiepileptic comedication on the single-dose pharmacokinetics of lamotrigine, 19 patients with epilepsy (10 comedicated with enzyme inducers and 9 comedicated with valproic acid) aged 8 months to 30 years received a single oral dose of lamotrigine (0.6 to 2.2 mg/kg) after an overnight fast. Blood samples were collected for at least 36 hours and plasma lamotrigine concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were calculated by noncompartmental analysis. Lamotrigine half-life (T1/2) and oral clearance (Cl/F) values were significantly lower and significantly higher, respectively, in patients comedicated with enzyme inducers than in those receiving valproic acid (T1/2 = 8.1 vs. 41.7 hours respectively, P < 0.001; Cl/F = 0.11 vs. 0.04 L/h per kg respectively, P < 0.005, geometric means), whereas Cmax and Tmax values were comparable in the two groups. The differences in pharmacokinetic parameters persisted when comparisons were made within subgroups stratified according to age. Within groups of patients homogeneous for type of comedication, Cmax and AUC values tended to be lower in children aged less than 12 years than in older patients. There was no significant relationship between half-life values and age. The authors conclude that both age and type of comedication influence lamotrigine pharmacokinetics. The reduction in lamotrigine concentrations caused by enzyme inducers and the elevation caused by valproic acid can be explained by stimulation and inhibition, respectively, of lamotrigine glucuronidation. On the other hand, the lower plasma lamotrigine levels in children than in adolescents and older patients may not be explainable solely by differences in metabolic rate.

Adolescent↗