Biomedical subjects

Emilio Perucca

Publications and source records attributed to Emilio Perucca.

52 records · Page 3Linked to original sources

PubMed2003

Current trends in antiepileptic drug therapy.

Over the last two decades, drug therapy for epilepsy has improved substantially. This can be ascribed to a large extent to three factors, including the demonstration of the advantages of monotherapy; the realization of the need for dosage tailoring, coupled [for some antiepileptic drugs (AEDs)] with control of pharmacokinetic variability through therapeutic drug monitoring; and the introduction of newer agents with improved tolerability profiles. What further advances should we expect for the future? Current trends that are expected to increasingly affect our prescribing patterns include greater reliance on evidence-based medicine and treatment guidelines, a trend that will be facilitated by completion of therapeutically meaningful randomized trials (including cost-effectiveness studies) and high-quality observational studies (including multinational pregnancy registries), as well as initiatives from scientific societies and government organizations aimed at condensing the most relevant information into therapeutic guidelines. The explosion in communication technology will accelerate dissemination of this information and its application to clinical practice. Other factors include a more rational patient-tailored AED selection and dose individualization, aided by characterization of predictors of outcome as defined by clinical parameters (sex, age, epilepsy syndrome, and etiology), pathophysiological mechanisms, and newly discovered genetic markers of outcome; improved definition of the role of new AEDs, resulting in their increased use in newly diagnosed epilepsy; and reappraisal of the value of combination therapy in refractory epilepsies, based on evidence produced by experimental and clinical studies designed to identify favorable pharmacodynamic interactions. Additional important developments may come from the discovery of novel, more efficacious AEDs and from exploration of potential new targets, such as prevention of epileptogenesis.

Anticonvulsants↗

PubMed2003

Plasma gabapentin concentrations in children with epilepsy: influence of age, relationship with dosage, and preliminary observations on correlation with clinical response.

The influence of age and administered daily dosage on the plasma concentrations of gabapentin (GBP) at steady state was evaluated in a group of 41 children and young adults (aged 3-30 years) receiving long-term adjunctive treatment with GBP for the management of refractory partial-onset seizures. For each patient, peak and trough concentrations were determined by a specific high-performance liquid chromatography (HPLC) method in samples obtained before the morning dose and 2.5 hours later, respectively. To assess within-subject relationship between plasma concentration and dosage, 30 patients were evaluated at more than one dosage level. Within the assessed dose range, plasma GBP concentrations were linearly related to dose. Apparent oral clearance values (mean +/- SD) in children aged 6 years or less (4.8 +/- 0.9 mL/kg/min) were comparable with those observed in children aged 7 to 15 years (4.6 + 1.5 mL/kg/min) and moderately higher than those found in young adults (3.9 + 0.9 mL/kg/min), even though differences among groups failed to reach statistical significance. There was, however, a significant difference in CL/F between children aged 10 years or less and older children (5.1 +/- 1.1 vs. 3.8 +/- 1.2 mL/kg/min, P < 0.005). Of the 41 patients who entered the study, 22 discontinued treatment, mostly due to insufficient efficacy. No significant difference in plasma GBP concentration was detected between patients showing a greater than 50% reduction in seizure frequency (4.1 +/- 1.9 microg/mL, n = 11, mean +/- SD) and those having no significant clinical improvement (4.4 +/- 1.7 microg/mL, n = 30). These results indicate that in children given dosages up to 50 mg/kg/d (mean, 25 mg/kg/d), GBP pharmacokinetic analyses show no important deviation from linearity. The data also suggest that, on average, children may need moderately higher dosages to reach plasma GBP concentrations comparable with those found in adults. There seems to be a large variation in the plasma concentrations of the drug associated with a favorable therapeutic response.

Acetates↗

PubMed2003

Analysis of topiramate and its metabolites in plasma and urine of healthy subjects and patients with epilepsy by use of a novel liquid chromatography-mass spectrometry assay.

A novel liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for quantification of topiramate (TPM) and its metabolites 10-hydroxy topiramate (10-OH-TPM), 9-hydroxy topiramate (9-OH-TPM), and 4,5-O-desisopropylidene topiramate (4,5-diol-TPM) in plasma and urine. The method uses 0.5 mL of plasma or 1 mL of urine that is extracted with diethyl ether and analyzed by LC-MS. Positive ion mode detection enables tandem mass spectrometric (MS/MS) identification of the aforementioned four compounds. Calibration curves of TPM, 4,5-diol-TPM, 9-OH-TPM, and 10-OH-TPM in plasma and urine were prepared and validated over the concentration range of 0.625 to 40 microg/mL using TPM-d(12) as an internal standard. Calibration curves were linear over this concentration range for TPM and its metabolites. Accuracy and precision ranged in urine from 83% to 114% and 4% to 13% (%CV), respectively, and in plasma from 82% to 108% and 6% to 13%, respectively. The applicability of the assay was evaluated by analyzing plasma samples from a healthy subject who received a single oral dose of TPM (200 mg) and urine samples from 11 patients with epilepsy treated with TPM (daily dose between 100 to 600 mg) alone or with other antiepileptic drugs. Only TPM was detected and quantified in the plasma samples, and its concentration ranged between 0.7 and 4.3 microg/mL. The concentrations of TPM and 10-OH TPM were quantifiable in all urine samples and ranged from 20 to 300 microg/mL for TPM and from 1 to 50 microg/mL for 10-OH-TPM. The metabolites 4,5-diol-TPM and 9-OH-TPM were also detected in all urine samples, but their concentrations were quantifiable only in 4 patients. An unidentified peak in the chromatograms obtained from patients' urine was attributed to 2,3-O-desisopropylidene topiramate (2,3-diol-TPM). Due to a lack of reference material of 2,3-diol TPM and the similar MS/MS spectrum with 4,5-diol-TPM, the calibration curves of 4,5-diol-TPM were used for the quantification of its isomer 2,3-diol-TPM. Based on these determinations, the apparent 2,3-diol-TPM-to-TPM concentration ratio in patients' urine ranged from 0.05 to 0.51 and the 10-OH-TPM-to-TPM ratio ranged from 0.02 to 0.17. In conclusion, a novel LC-MS method for the assay of TPM and four of its metabolites in plasma and urine was developed. Its utilization for analysis of urine samples from patients with epilepsy showed that the method was suitable for analysis of TPM and its metabolites in clinical samples. Two quantitatively significant TPM metabolites (10-OH-TPM and 2,3-diol-TPM) and two quantitatively minor metabolites (9-OH-TPM and 4,5-diol-TPM) were detected and quantified in urine samples from patients with epilepsy.

Adult↗

PubMed2003

Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response.

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59, P < 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73, P < 0.0001). In particular, CL/F values in children aged less than 10 years (112 +/- 82 mL/kg/h, mean +/- SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 +/- 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 +/- 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 +/- 2.2 micrograms/mL, n = 30) and those having no clinical improvement (5.2 +/- 2.2 micrograms/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.

Adolescent↗

PubMed2003

The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come?

The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.

Acetates↗

PubMed2002

Overtreatment in epilepsy: adverse consequences and mechanisms.

The most important determinant of quality of life in patients with epilepsy is complete seizure control, and therefore this should be the ultimate goal of pharmacological therapy. Seizure freedom, or a reduction in seizure frequency, however, should not be sought at all costs, and the situation should never arise where a person with epilepsy is made to suffer more from the side effects of treatment than from the consequences of the underlying disease. Overtreatment is not uncommon in patients taking antiepileptic drugs, and it may occur in many forms and with a variety of mechanisms. Long-term use (or continuation) of anticonvulsant therapy in situations where it is not indicated (e.g. in children with simple febrile seizures, or in non-epileptic seizure-free patients who underwent brain surgery) constitutes a blatant case of overtreatment. Other forms of overtreatment include the use of unnecessarily fast dose escalation rates, which may expose the patient to potentially serious or severe side effects, or the prescription of unnecessarily high maintenance dosages. The latter occurrence may result from inadequate understanding of dose-response relationships, from misinterpretation of serum drug concentrations (e.g. targeting concentrations within the 'range' in patients who are well controlled at lower concentrations) or, at times, from failure to recognize a paradoxical increase in seizure frequency as a manifestation of drug toxicity. The most common form of overtreatment, however, involves the unnecessary use of combination therapy (polypharmacy) in patients who could be treated optimally with a single drug. Adverse effects associated with polypharmacy often result from undesirable drug-drug interactions. While pharmacokinetic interactions are somewhat predictable and can be minimized or controlled by monitoring serum drug concentrations and/or dose adjustment, pharmacodynamic interactions leading to enhanced neurotoxicity (as seen, for example, in some patients given a combination of lamotrigine and carbamazepine) can only be identified by careful clinical observation. There is evidence that not all antiepileptic drug combinations are equally adverse, and that the combined use of specific drugs (e.g. lamotrigine and valproic acid) may even exhibit an improved therapeutic index compared with either agent given alone, provided appropriate dose adjustments are made. Although the suggestion has been made that adverse effects are more likely to result from combining anticonvulsants having a similar mode of action, our knowledge of the pharmacology of individual agents is insufficient to allow a reliable prediction of the clinical effects of specific drug combinations.

Anticonvulsants↗

PubMed2002

Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs.

As antiepileptic drugs (AEDs) and psychotropic agents are increasingly used in combination, the possibility of pharmacokinetic interactions between these compounds is relatively common. Most pharmacokinetic interactions between AEDs and psychoactive drugs occur at a metabolic level, and usually involve changes in the activity of the cytochrome P450 mixed-function oxidases (CYP) involved in their biotransformation. As a consequence of CYP inhibition or induction, plasma concentrations of a given drug may reach toxic or subtherapeutic levels, and dosage adjustments may be required to avoid adverse effects or clinical failure. Enzyme-inducing AEDs, such as carbamazepine (CBZ), phenytoin (PHT), and barbiturates, stimulate the oxidative biotransformation of many concurrently prescribed psychotropics. In particular, these AEDs may decrease the plasma concentrations of tricyclic antidepressants, many antipsychotics, including traditional compounds, i.e., haloperidol and chlorpromazine, and newer agents, i.e., clozapine, risperidone, olanzapine, quetiapine, and ziprasidone, and some benzodiazepines. Conversely, new AEDs appear to have a lower potential for interactions with all psychotropic drugs. While antipsychotics and anxiolytics do not significantly influence the pharmacokinetics of most AEDs, some newer antidepressants, such as viloxazine, fluoxetine, and fluvoxamine, may lead to higher serum levels of some AEDs, namely CBZ and PHT, through inhibition of CYP enzymes. No significant pharmacokinetic interactions have been documented between AEDs and lithium. Information about CYP enzymes responsible for the biotransformation of individual agents and about the effects of these compounds on the activity of specific CYP enzymes may help in predicting and avoiding clinically significant interactions. Apart from careful clinical observation, serum level monitoring of AEDs and psychotropic drugs can be useful in determining the need for dosage adjustments, especially if there is any change in seizure control, or possible toxicity.

Animals↗

PubMed2002

Add-on phenytoin fails to prevent early seizures after surgery for supratentorial brain tumors: a randomized controlled study.

PURPOSE: To determine the potential effectiveness of phenytoin (PHT) in preventing early postoperative seizures in patients undergoing craniotomy for supratentorial brain tumors. METHODS: Two hundred patients requiring elective craniotomy for supratentorial brain tumors were randomized to two groups of equal size, with a prospective, open-label, controlled design. One group received PHT (18 mg/kg as an intravenous intraoperative load, followed by additional daily doses aimed at maintaining serum PHT concentrations within the 10- to 20-aeg/ml range) for 7 consecutive days. In the other group, PHT was not administered. More than 90% of patients in both groups continued to take preexisting anticonvulsant medication (AEDs) with carbamazepine or phenobarbital throughout the study. The primary efficacy end point was the number of patients remaining free from seizures during the 7-day period after the operation. RESULTS: Of 100 patients allocated to PHT, 13 experienced seizures during the 7-day observation period, compared with 11 of 100 patients in the placebo group (p > 0.05). Most seizures occurred in the first day after surgery in both groups. There were no differences between groups in the proportion of patients experiencing more than one seizure, but there was a trend for generalized seizures to be more common in PHT-treated patients than in controls (11 vs. five patients, respectively). Status epilepticus occurred in one patient in the PHT group and in two patients in the control group. Of the 13 PHT-treated seizure patients, 11 had serum PHT concentrations within the target range, and only two had concentrations below range on the days their seizures occurred. CONCLUSIONS: PHT, given at dosages producing serum concentrations within the target range, failed to prevent early postoperative seizures in patients treated with concomitant AEDs. Prophylactic administration of PHT cannot be recommended in these patients.

Adolescent↗

PubMed2002

What can we learn from clinical trials of anticonvulsant drugs in epilepsy?

Any physician who intends to utilize the available antiepileptic drugs (AEDs) judiciously, cannot do so without being well versed on their pharmacological properties and the large body of evidence that is continuously accumulating on their relative efficacy and tolerability in different types of epilepsy. While informal observations such as retrospective surveys and case reports can be useful under special circumstances, prospective randomized clinical studies represent by far the most important tool by which objective information can be obtained about the clinical value of existing drugs. Even randomized trials, however, can produce misleading conclusions because of inherent weaknesses or bias in study design, analysis, and interpretation. Common deficiencies identified in some of the most recent drug trials in epilepsy include 1) inclusion of inappropriately heterogeneous patient groups (for example, patients with partial and primarily generalized seizures); 2) low statistical power due to insufficient sample size (for trials designed to show therapeutic equivalence); 3) inappropriate titration rates or suboptimal dosages or dosing schedules (often favouring the sponsor's product over the comparator); 4) insufficient duration of treatment; and 5) utilization of endpoints of questionable clinical significance. In part, some of the above shortcomings can be ascribed to the fact that most clinical drug trials are designed to address regulatory needs rather than to provide the type of information required for rational prescribing. Physicians need to be alerted about the importance of these issues, and they should make every possible effort to interpret critically the medical literature on which they rely to guide and support their therapeutic decisions.

Anticonvulsants↗

PubMed2002

Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction.

The effect of fluoxetine on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was evaluated in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized on risperidone (4-6 mg/day) received additional fluoxetine (20 mg/day) to treat concomitant depression. One patient dropped out after 1 week due to the occurrence of akathisia associated with markedly increased plasma risperidone concentrations. In the other subjects, mean plasma concentrations of risperidone increased during fluoxetine administration from 12 +/- 9 ng/mL at baseline to 56 +/- 31 at week 4 (p < 0.001), while the levels of 9-OH-risperidone were not significantly affected. After 4 weeks of combined treatment, the levels of the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) increased by 75% (range, 9-204%, p < 0.01) compared with baseline. The mean plasma risperidone/9-OH-risperidone ratio also increased significantly. During the second week of adjunctive therapy, two patients developed Parkinsonian symptoms, which were controlled with anticholinergic medication. These findings indicate that fluoxetine, a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a less potent inhibitor of CYP3A4, reduces the clearance of risperidone by inhibiting its 9-hydroxylation or alternative metabolic pathways. This interaction may lead to toxic plasma risperidone concentrations. In addition to careful clinical observation, monitoring plasma risperidone levels may be of value in patients given adjunctive therapy with fluoxetine.

Adult↗

PubMed2002

Marketed new antiepileptic drugs: are they better than old-generation agents?

Until a decade ago, the pharmacologic armamentarium for the management of epilepsy was restricted to a little more than a handful of drugs that had been introduced 20 to 70 years earlier. This situation has changed dramatically, with as many as nine new-generation drugs (oxcarbazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide, vigabatrin, and felbamate, in addition to the water-soluble phenytoin prodrug fosphenytoin) having been introduced in Europe, the United States, or other parts of the world. These drugs represent a welcome addition because they produce an appreciable reduction in seizure frequency in up to 40% to 50% of patients who had been refractory to older-generation drugs. However, only a few patients with truly refractory disease can be made seizure-free by these new drugs, and the search for more effective anticonvulsants should continue. Although in patients with newly diagnosed epilepsy the efficacy of new-generation drugs is not superior to that of older agents, some of the newer drugs offer advantages in terms of improved tolerability, ease of use, and reduced interaction potential. However, the increased availability of treatment options implies that drug choice in patients with epilepsy is more complicated than in the past, and there is a concern that inadequate knowledge of indications, contraindications, and mode of use of the newer drugs could result in some patients receiving suboptimal treatment or being exposed to undue risks from side effects and drug interactions. Although measurement of plasma drug concentrations is often used to adjust the dosage of classic antiepileptic drugs, therapeutic drug monitoring has been claimed to be of little or no value with newer-generation drugs. This view has been challenged in light of the evidence that pharmacokinetic variability contributes to an important extent to differences in dosage requirements for most of these drugs.

Anticonvulsants↗

PubMed2002

Plasma concentrations of the enantiomers of fluoxetine and norfluoxetine: sources of variability and preliminary observations on relations with clinical response.

Factors affecting the plasma concentrations of the R- and S-enantiomers of fluoxetine and norfluoxetine were investigated in 131 adult patients receiving long-term fluoxetine, of 10 to 60 mg/d (mean, 24 +/- 10 mg/d). Plasma concentration values (geometric means, CI 95%) in these patients were 186 (156, 223) nmol/L for S-fluoxetine, 67 (58, 77) nmol/L for R-fluoxetine, 247 (212, 287) nmol/L for S-norfluoxetine, and 118 (102, 137) nmol/L for R-norfluoxetine. The difference between the concentrations of the respective R- and S-enantiomers was statistically significant ( P< 0.0001) for both the parent drug and the demethylated metabolite. A significant correlation was found between the concentrations of each enantiomer and the prescribed daily dosage (r = 0.44, P< 0.0001 for S-fluoxetine; r = 0.48, P < 0.0001 for R-fluoxetine; r = 0.36, < 0.0001 for S-norfluoxetine; r = 0.32, P = 0.0003 for R-norfluoxetine), but the variability in concentration at any given dosage was considerable. When an iterative model based on multiple polynomial regressions was applied to determine the potential contributions of dosage, age, gender, body weight, and concomitant medication to the variability in the plasma concentration of the enantiomers, dosage was consistently found to provide the greatest predictive value. The predictive value of the model could be consistently improved when concentrations of other enantiomers were included as covariates. Of 58 patients with depressive symptoms for whom evaluation of clinical response (CGI scale) was available, 33 (57%) responded favorably to treatment. The plasma levels of individual enantiomers and of the active moiety (ActM, sum of the concentrations of R-fluoxetine, S-fluoxetine, and S-norfluoxetine) in these patients did not differ significantly from those found in patients with unsatisfactory therapeutic response. Likewise, the concentrations of individual enantiomers and of the ActM were similar in patients with or without adverse effects. Overall, these results demonstrate that the pharmacokinetics of fluoxetine and norfluoxetine exhibit marked stereoselectivity and considerable interpatient variability, which could not be explained by differences in gender, age, or comedication. In addition, a considerable variability was found in the enantiomers' concentrations associated with a favorable therapeutic response.

Adolescent↗

PubMed2002

Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience.

Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission. Valproate is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. In particular, sustained-release formulations are available that minimise fluctuations in serum drug concentrations during a dosing interval and can therefore be given once or twice daily. Valproic acid is about 90% bound to plasma proteins, and the degree of binding decreases with increasing drug concentration within the clinically occurring range. Valproic acid is extensively metabolised by microsomal glucuronide conjugation, mitochondrial beta-oxidation and cytochrome P450-dependent omega-, (omega-1)- and (omega-2)-oxidation. The elimination half-life is in the order of 9 to 18 hours, but shorter values (5 to 12 hours) are observed in patients comedicated with enzyme-inducing agents such as phenytoin, carbamazepine and barbiturates. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase by this mechanism the plasma concentrations of certain coadministered drugs, including phenobarbital (phenobarbitone), lamotrigine and zidovudine. Valproate is a broad spectrum AED, being effective against all seizure types. In patients with newly diagnosed partial seizures (with or without secondary generalisation) and/or primarily generalised tonic-clonic seizures, the efficacy of valproate is comparable to that of phenytoin, carbamazepine and phenobarbital, although in most comparative trials the tolerability of phenobarbital was inferior to that of the other drugs. Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Many of these syndromes are associated with multiple seizure types, including tonic-clonic, myoclonic and absence seizures, and prescription of a broad-spectrum drug such as valproate has clear advantages in this situation. A number of reports have also suggested that intravenous valproate could be of value in the treatment of convulsive and nonconvulsive status epilepticus, but further studies are required to establish in more detail the role of the drug in this indication. The most commonly reported adverse effects of valproate include gastrointestinal disturbances, tremor and bodyweight gain. Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonaemia), platelet disorders, pancreatitis, liver toxicity (with an overall incidence of 1 in 20,000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy) and teratogenicity, including a 1 to 3% risk of neural tube defects. Some studies have also suggested that menstrual disorders and certain clinical, ultrasound or endocrine manifestations of reproductive system disorders, including polycystic ovary syndrome, may be more common in women treated with valproate than in those treated with other AEDs. However, the precise relevance of the latter findings remains to be evaluated in large, prospective, randomised studies.

Anticonvulsants↗

PubMed2002

Epilepsy in elderly people: management issues.

Epilepsy in elderly people is far more common than many doctors realise. The prevalence and incidence are frequently underestimated due to underdiagnosis or misdiagnosis of the condition. As the proportion of older people in the population grows, the management of epilepsy in this population will become increasingly important. Elderly people are especially susceptible to the consequences of seizures, particularly loss of self-confidence, decreased independence, and "falls" resulting in physical injury. Establishing the diagnosis of epilepsy in old age can be more difficult than in younger patients due to the extensive range of differential diagnoses and a far higher prevalence of concomitant disease. Treatment strategies are demanding; they must allow for the complexities of co-morbidity, co-medication, alterations in drug handling, and drug effects on an aging body. Together with a growing array of antiepileptic medication from which to choose, these factors make the management of epilepsy in elderly people particularly challenging.

Aged↗

PubMedDate not supplied

Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data.

The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/F) in 75 patients aged 65-90 years (mean, 71.7 +/- 5.3 years) receiving phenytoin alone (n = 58) or in combination with phenobarbital (n = 17) and in an equal number of control patients aged 20-50 years (mean, 36.7 +/- 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/F values compared with controls (14.6 +/- 4.7 ml h(-1) kg(-1) versus 13.1 +/- 4.2 ml h(-1) kg(-1), P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 +/- 1.1 mg kg(-1)day(-1) versus 5.3 +/- 1.1 mg kg(-1) day(-1), P < 0.001) and had lower serum phenytoin concentrations (14.1 +/- 5.7 microg ml(-1) versus 18.6 +/- 6.8 microg ml(-1), P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/F. By contrast, in the elderly group, CL/F values were negatively correlated with age. On average, CL/F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug. Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.

Adult↗

PubMedDate not supplied

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

The Seventh Eilat Conference on New Antiepileptic Drugs (AEDs) (EILAT VII) took place in Villasimius, Sardinia, Italy from the 9th to 13th May 2004. Basic scientists, clinical pharmacologists and neurologists from 24 countries attended the conference,whose main themes included advances in pathophysiology of drug resistance, new AEDs in pediatric epilepsy syndromes, modes of AED action and spectrum of adverse effects and a re-appraisal of comparative responses to AED combinations. Consistent with previous formats of this conference, the central part of the conference was devoted to a review of AEDs in development, as well as updates on second-generation AEDs. This article summarizes the information presented on drugs in development, including atipamezole, BIA-2-093, fluorofelbamate, NPS 1776, pregabalin, retigabine, safinamide, SPM 927, stiripentol, talampanel,ucb 34714 and valrocemide (TV 1901). Updates on felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine,topiramate, vigabatrin, zonisamide, new oral and parenteral formulations of valproic acid and SPM 927 and the antiepileptic vagal stimulator device are also presented.

Adult↗