Are serum anticonvulsant levels in people with epilepsy appropriately monitored?

The medical care of people with epilepsy has often been described as being poor, although objective markers for the quality of epilepsy care are lacking. This paper describes the results of using a simple quality marker, appropriate measuring of serum anticonvulsant levels, in assessing the quality of epilepsy care. The checking of serum phenytoin levels in certain clinical circumstances is advocated, whereas the checking of serum sodium valproate levels is not generally supported. A total of 1254 people with epilepsy in the community had their medical records examined for evidence of checking of anticonvulsant levels and 1204 of these individuals completed questionnaires about their epilepsy and its treatment. Of those on phenytoin, only 26% to 47% had phenytoin levels checked appropriately; 23% of patients on sodium valproate were inappropriately having their serum levels checked. The only clinical or organizational factor that predicted whether checking of serum phenytoin levels was performed was whether or not patients reported three common phenytoin side-effects but this still showed a small effect size (odds ratio 2.4).

Proof of efficacy trials: cross-over versus parallel-group.

In recent years, most of the published trials of new antiepileptic drugs (AEDs) have had a parallel-group design rather than cross-over. Nevertheless, in some situations the cross-over trial does have advantages, and therefore, its role needs re-appraisal. The crossover design requires a much smaller number of patients for a similar statistical power because patients act as their own controls, which is a particular advantage when the type or severity of epilepsy varies widely in the patients recruited. As a result, the financial cost is smaller and fewer patients are exposed to the new agent, perhaps with ethical arguments in favour of this type of design in proof-of-efficacy trials. Within-patient analysis also makes the detection of drug interactions more robust. On the other hand, there is a theoretical risk that the beneficial effects of the first treatment (or conversely, withdrawal seizures on stopping it) might carry over into the second treatment period and thereby confound the detection of treatment effects. The parallel-group design is more versatile in that a stable disease state is not a pre-requisite, and therefore, trials in newly diagnosed patients are possible. Multiple treatment limbs are also more practical. The duration of a parallel-group trial may be shorter because only one treatment period is involved, although this may be offset by the much larger number of patients needed to be recruited and the time involved in doing so. Parallel-group trials almost always require a multicentre approach, with the inevitable logistic problems involved. It is argued that proof-of-principle and add-on proof-of-efficacy trials of a new drug are more efficiently undertaken using a cross-over design but that subsequent evaluation will require the versatility of trials with a parallel-group design.

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.

Relation between dosage of carbamazepine and concentration in hair and plasma samples from a compliant inpatient epileptic population.

Compliance is a problem in all areas of therapeutic medicine. Methods for its assessment are classified as either indirect or direct. Indirect assessment is based on criteria such as pill counts, questionnaires, and self-reporting; direct methods involve the analytic measurement of the drugs in biologic fluids such as plasma or urine. Drugs taken either therapeutically or recreationally become incorporated into hair. This prospective study investigated the relation between the daily intake of the antiepileptic drug carbamazepine and both its trough plasma and hair concentrations in a highly supervised inpatient population of patients with epilepsy during a period of 6 months. Results showed that although there was a significant variation between patients resulting from the substantial range in the daily intake of carbamazepine (800-2400 mg/day), the intrapatient variation in both trough plasma and hair concentrations during the 6-month period were not significantly different. The mean intrapatient percentage coefficient of variation in total plasma and hair concentrations of carbamazepine was 11.5 +/- 4.7 and 15.0 +/- 5.2, respectively, both of which were independent of the daily dosage. This relatively small intrapatient variation in hair concentration over time and its close relation to the plasma concentration suggests that hair analysis may be a complementary and useful technique in monitoring drug-taking behavior.

A placebo-controlled, double-blind cross-over trial of adjunctive one month remacemide hydrochloride treatment in patients with refractory epilepsy.

The efficacy, safety and pharmacokinetics of adjunctive remacemide hydrochloride, a novel, low-affinity non-competitive NMDA receptor channel blocker, were investigated in 28 adult patients with refractory epilepsy. This was a randomized double-blind placebo-controlled cross-over study with five 4-week periods (baseline, treatment 1, washout, treatment 2, washout). Baseline median seizure frequency was reduced by 33% following adjunctive remacemide hydrochloride 150 mg q.i.d. for 4 weeks compared with placebo (P= 0.041). Seizure frequency was reduced by > or =50% in 30% of patients treated with remacemide hydrochloride compared with 9% on placebo. Mean plasma concentration of concomitant carbamazepine increased by approximately 15% following adjunctive remacemide hydrochloride. There was no correlation between increased plasma carbamazepine and reduced seizure frequency. Remacemide hydrochloride was well tolerated and only three patients withdrew due to adverse events (two remacemide hydrochloride, one placebo). Two patients died unexpectedly from their epilepsy during placebo treatment; both deaths were considered by the investigators to be unrelated to earlier remacemide hydrochloride treatment. This first specific efficacy investigation with adjunctive remacemide hydrochloride demonstrated anticonvulsant effects in patients with refractory epilepsy. More extensive clinical investigation is justified.

The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction.

PURPOSE: To assess the comparative therapeutic value of valproate (VPA), lamotrigine (LTG), and their combination in patients with complex partial seizures resistant to other established antiepileptic drugs (AEDs). METHODS: After a 3-month prospective baseline, 20 adults with refractory complex partial seizures not exposed previously to VPA and LTG were scheduled to receive three consecutive add-on treatments with VPA, LTG, or their combination, according to an open, response-conditional, crossover design. Each period consisted of a 6- to 12-week dose optimization followed by 3-month evaluation at stabilized serum drug levels. Only patients not responding to one phase proceeded to the next. RESULTS: A >50% reduction in seizure frequency was observed in three of 20 patients given VPA and in four of 17 patients given LTG. Of the remaining 13 patients, four became seizure free, and an additional four experienced seizure reductions of 62-78% when VPA and LTG were given in combination. Mild tremor was observed in three patients receiving VPA and in all patients taking the VPA--LTG combination. In patients responding to combination therapy, optimized dosages and peak serum levels of both VPA and LTG were lower than those during separate administration. CONCLUSIONS: A considerable proportion of patients who failed to respond to VPA and LTG separately improved when the two drugs were combined, although serum levels of both agents were lower during combination therapy. Despite methodologic limitations in the nonrandomized treatment sequence, these findings suggest that VPA and LTG exhibit a favorable pharmacodynamic interaction in patients with refractory partial epilepsy. The dosage of both drugs, however, may need to be reduced to minimize the risk of intolerable side effects.

Lamotrigine-associated rash: risk/benefit considerations in adults and children.

PURPOSE: Lamotrigine (LTG) is an antiepileptic drug (AED) recently released in several countries. It is effective for a variety of seizure types in adults and children both as an add-on agent and in monotherapy, and is generally well tolerated. This report reviews the apparent risk factors for rash associated with LTG to determine whether and how the risk of serious rash can be minimized in practice. METHODS: The panel of experts reviewed all published and unpublished data related to the incidence and risk factors for serious rash with LTG. RESULTS: An allergic skin reaction occurs in approximately 10% of patients, usually in the first 8 weeks. Rashes leading to hospitalization, including Stevens-Johnson syndrome and hypersensitivity syndrome, occurred in approximately one of 300 adults and one of 100 children in clinical trials and appeared to be increased with overrapid titration when starting therapy and with concurrent valproate (VPA). CONCLUSIONS: Recommendations are made for both minimizing the likelihood of serious rash and for management of rash in patients taking LTG. Risk of serious rash may possibly be lessened by strict adherence to manufacturer's dosing guidelines, particularly in patients who are at higher risk: those on concurrent VPA and in the pediatric population.

Once-daily versus twice-daily vigabatrin: is there a difference? The results of a double-blind pilot study.

PURPOSE: Vigabatrin (VGB) has been approved in Europe and is prescribed for either once or twice-daily administration. This choice has been based on the pharmacodynamic activity of VGB. The purpose of this study was to compare the efficacy and tolerability of these two different medication regimens. METHODS: The study design was a double-blind randomized two-period cross-over study in adults who had responded to add-on VGB for previously uncontrolled seizures. Each study period consisted of three months. Patients were maintained on the same daily dose of VGB to which they had demonstrated a clinical response. In addition to the primary efficacy criteria of seizure frequency on the two treatment regimens, this study included blinded ratings of overall efficacy and "well being" by both physician and patient. The primary tolerability criterion was the reported incidence of adverse events by phase. RESULTS: Fifty patients were initially entered into the study, and 13 patients withdrew before completion, only one reported as due to an adverse event. There was no statistical difference in seizure frequency or the tolerability of the medication. Blinded physician and patient rating scales for seizure control, and patient well being showed a nonstatistical trend toward once-daily administration as compared with twice-daily administration. CONCLUSIONS: This clinical study provides support for the pharmacological evidence that this preparation may be administered on a once or twice daily basis, depending on the individual patient's preference, total dosage and co-medication.

Attitudes of GPs to the care of people with epilepsy.

BACKGROUND: Most individuals with current epilepsy are solely under the care of the primary care team for follow-up care. Government working party recommendations, expert epilepsy panels and patients have also stressed the central role of the GP in follow-up care. Problems in the provision of care in the community have, however, repeatedly been highlighted. The views of GPs about service provision for people with epilepsy may be an important barrier to providing care, but have not yet been studied in a systematic manner. OBJECTIVES: We aimed to ascertain the views of GPs on service provision for people with epilepsy in primary care and on specific initiatives to improve care. METHOD: A specially designed postal questionnaire was sent to all 262 GPs on the list of West Glamorgan FHSA. It ascertained what GPs felt their role should be in providing care to people with epilepsy, identified their views on the importance of particular problems in providing this care, as well as obtaining their opinions on possible future initiatives to improve epilepsy care in the community. RESULTS: The overall response rate was 70%. Although a majority of responding GPs (55%) agreed that the care of people with epilepsy should be based in general practice, 23% disagreed. A lack of confidence about knowledge of epilepsy (34% responders), unfamiliarity with new drugs (65% responders) and a lack of time (41% responders) were identified as important perceived barriers to providing epilepsy care. Nearly all responding GPs would welcome guidelines for epilepsy care (93% felt they would be very helpful) and an epilepsy liaison nurse in the community was the most popular option in terms of preferred overall strategy for improving care. CONCLUSIONS: Despite 40 years of official recommendations regarding the central role of the GP in the follow-up care of people with epilepsy, a number of GPs have difficulty in providing this care. Many feel that they lack knowledge or are too time pressured to improve the situation. Nearly all GPs say that they would find guidelines for epilepsy care very helpful and over half would find epilepsy liaison nurses helpful. There is scope for more innovative ideas for epilepsy care in the community.

Absence of interaction between tiagabine, a new antiepileptic drug, and the benzodiazepine triazolam.

In a randomised, double blind, placebo-controlled, four-period cross-over study in 12 healthy volunteers, the potential pharmacodynamic and pharmacokinetic interactions between the new antiepileptic drug, tiagabine, and the benzodiazepine, triazolam, were investigated. A single dose of tiagabine HCl 10 mg did not enhance the sedative or cognitive effects of a single dose of the benzodiazepine triazolam 0.125 mg, although the time-course of the effects was prolonged. Furthermore, tiagabine did not produce any statistically significant effects on the pharmacokinetics of triazolam. Similarly, the pharmacokinetics of tiagabine were not modified by triazolam. Tiagabine was well tolerated when administered alone or with triazolam.

Single and multiple dose pharmacokinetics of felbamate in the elderly.

AIMS: The objective of this study was to compare the pharmacokinetics, safety and tolerability of the antiepileptic drug felbamate in young and elderly healthy vounteers. METHODS: The single and multiple dose pharmacokinetics of felbamate were examined in an open-label two-dose level parallel group study in 24 elderly (66 to 78-year-old) and 11 young (18 to 45-year-old) healthy volunteer subjects. Pharmacokinetics were determined from blood samples obtained over 120 h after administration of single 600 mg or 1200 mg doses, and after multiple doses of 600 mg or 1200 mg administered every 12 h. Safety and tolerability were assessed through laboratory tests, ECGs, vital signs and reported adverse events. RESULTS: Single dose felbamate pharmacokinetic parameters differed between young and elderly subjects; compared with young subjects, elderly subjects had lower mean clearance (31.2 vs 25.1 ml min(-1); 90% CI -11.4 to -0.9; P = 0.02) and a trend towards a greater half-life (18.6 vs 21.0 h; 90% CI -0.6 to 5.4; P = 0.11). Mean AUC and C(max) values were also higher in elderly subjects. No gender differences were noted for weight-adjusted pharmacokinetic variables. Felbamate was less well tolerated in elderly subjects compared with young subjects, as shown by higher rates of adverse event reporting and dropouts at the higher dose level. This may be due to age-related pharmacokinetic differences, to the rapid dose titration schedule used in this study, and/or to altered sensitivity to felbamate's pharmacodynamic effects. CONCLUSIONS: These findings imply that elderly subjects require lower initial dosing and slower dose titration of felbamate than non-elderly subjects.

Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q.

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.

Lack of pharmacokinetic interaction between remacemide hydrochloride and sodium valproate in epileptic patients.

A randomized, double-blind, placebo-controlled cross-over study of adjuvant treatment with remacemide hydrochloride was carried out in 17 patients taking sodium valproate (VPA) as monotherapy. Plasma concentration profiles of VPA, remacemide, and its active desglycinyl metabolite (ARL12495XX) were determined following single (300 mg) and multiple dosing (150 or 300 mg twice daily) of remacemide hydrochloride for 14 days with a 300-mg final dose. Central nervous system side-effects were more common at the higher dose, which prompted dosage reduction to 150 mg twice daily for subsequent patients partway through the study. The mean area under the concentration-time curve, peak concentration and pre-dose concentration of VPA were unchanged by remacemide hydrochloride in three patients on the higher and in 10 patients on the lower dose of remacemide. The pharmacokinetic parameters of remacemide and its active metabolite in the VPA-treated patients were similar to those described previously in healthy volunteers. Thus, remacemide hydrochloride does not interfere with the pharmacokinetics of VPA and vice versa.

Evidence for both in vivo and in vitro interaction between vigabatrin and alanine transaminase.

AIMS: Decreases in plasma alanine transaminase (ALA-T) activity of 20-100% have been reported following the use of vigabatrin (Sabril) in patients with uncontrolled epilepsy. This effect has a potential clinical significance as it may mask signs of early, underlying hepatic disease. It is particularly significant in a patient population known to have a higher than average risk of hepatotoxicity due to treatment with other anti-epilepsy drugs or to an independent, but concomitant, disease process. Vigabatrin is a highly specific enzyme antagonist. There is an almost 1000-fold difference between its activity against gamma-amino butyric acid aminotransaminase and ALA-T. However, some activity against other transaminases is not unexpected, and it, is important to determine the degree of vigabatrin's effect against ALA-T in man. METHODS: Two in vitro experiments, using serum samples spiked with vigabatrin, confirmed the presence of an interaction between vigabatrin and ALA-T, and formed the basis for the design of a study in five healthy male volunteers, in whom serum ALA-T activity was measured before and after a single dose of 1.5 g of vigabatrin. RESULTS: Serial sampling confirmed the presence of an in vivo interaction between vigabatrin and ALA-T, causing an inhibition of enzyme activity of 30-40%. A further 20% reduction was found in vitro in samples taken at the time of the peak plasma vigabatrin concentration after they had been stored for 6 h. CONCLUSIONS: The clinical significance of these findings is that the levels of ALA-T activity determined in patients receiving vigabatrin may be inaccurate. The "real' values must be assumed to be higher than those reported after routine testing. To obtain the most relistic measurement of ALA-T activity in patiets, samples should be taken at the times of trough plasma concentration and processed as soon as possible afterwards. Samples stored for any length of time at or above room temperature may also give even more false results.

Mutual interaction between remacemide hydrochloride and phenytoin.

A randomised, double-blind, placebo-controlled crossover study of add-on remacemide hydrochloride was carried out in epilepsy patients being treated with phenytoin (PHT) monotherapy. Eleven patients were recruited, ten of whom completed the study. Plasma concentration profiles of PHT, remacemide, and its active desglycinyl metabolite (ARL12495XX) were determined following single and multiple dosing with remacemide hydrochloride. Following 14 days' treatment with remacemide hydrochloride 300 mg twice daily, the mean AUC of PHT was increased by 11.5% (P = 0.33), Cmax by 13.7% (P = 0.32) and Cmin by 22.2% (P = 0.12) over placebo. There was an increase in trough concentrations of PHT averaging 20% during active treatment compared with placebo (P = 0.01). No symptoms of PHT toxicity were reported by any patient. There was no evidence of autoinduction of remacemide metabolism. However, average concentrations of remacemide and its active metabolite in PHT-treated patients were around 40 and 30% lower, respectively than in healthy volunteers previously receiving the same dose of remacemide hydrochloride. Thus, remacemide hydrochloride has a small inhibitory effect on PHT metabolism, which itself induces that of remacemide and its active metabolite. This mutual interaction is predictable and modest and should not present a barrier to their clinical use in combination.

The effect of losigamone (AO-33) on electrical activity and excitatory amino acid release in mouse cortical slices.

1. Losigamone is a novel anticonvulsant the mechanism of action of which is not known. This study investigated the effect of losigamone on spontaneous, NMDA- and AMPA-induced depolarizations in the cortical wedge preparation of the DBA/2 mouse (which are susceptible to sound-induced seizures) and on endogenous amino acid release from BALB/c mouse cortical slices. 2. Cortical wedges exhibit spontaneous depolarizations in magnesium-free medium and losigamone was effective in significantly reducing these spontaneous depolarizations at concentrations of 100 microM and above. 3. NMDA-induced depolarizations were significantly reduced by losigamone at concentrations of 25 microM and above. Losigamone had no effect on AMPA-induced depolarizations. 4. Veratridine (20 microM) and potassium (60 mM) were used to stimulate the release of amino acids from mouse cortex. Veratridine-stimulated release of glutamate was significantly reduced by losigamone at concentrations of 100 microM and above, while potassium-stimulated release was significantly reduced by losigamone at 200 microM. 5. NMDA antagonism and inhibition of excitatory amino acid release may contribute to the anticonvulsant effect of losigamone.

The pharmacokinetics of tiagabine in healthy elderly volunteers and elderly patients with epilepsy.

The pharmacokinetics of tiagabine after single-dose (8 mg) and multiple-dose (3 mg, three-times daily for four days) administration of tiagabine HCl were investigated in healthy elderly volunteers (n = 8; Group 1), elderly patients with epilepsy receiving at least one hepatic enzyme-inducing antiepileptic drug (AED) (n = 8; Group 2), and healthy young volunteers (n = 8; Group 3). Participants were matched by gender, age (Groups 1 and 2), alcohol intake, body weight, and whether they smoked tobacco. The pharmacokinetic parameters of tiagabine following single- and multiple-dose administration were similar in both healthy elderly and young volunteers except for a small but significant difference in the area under the concentration-time curve after multiple-doses (103 +/- 29 ng.hr/mL/mg in the elderly versus 72 +/- 20 ng.hr/mL/mg in younger participants). This is not expected to have any clinical relevance because of the large intersubject variability in this parameter. In contrast, and as expected, the pharmacokinetics of tiagabine were altered in the presence of enzyme-inducing antiepileptic drugs: Time to reach maximum plasma concentration, area under the concentration-time curve, and elimination half-lives were significantly lower (e.g. 39 +/- 13 ng.hr/mL/mg for AUC after multiple-dose) compared with corresponding values in the healthy volunteers. These findings suggest that adjusting the dose of tiagabine on the basis of the age of the patient is not necessary, although, irrespective of age, higher doses and/or more frequent administrations will be required in patients taking concomitant enzyme-inducing antiepileptic drugs.