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Therapeutic drug monitoring of a variety of antiepileptic drugs is used routinely as a guide to individualising the drug treatment of patients with epilepsy. Thin dry film multilayer immunoassays (OPUS) for carbamazepine, phenytoin, phenobarbitone, and valproic acid were evaluated and compared with fluorescence polarisation immunoassay (TDx), using commercially available control material and patient sera. For the OPUS, the within-batch coefficient of variation (CV) for the different drugs in the control material varied between 3.9% (phenobarbitone) and 8.1% (valproic acid). The between-batch CVs varied between 5.3% (valproic acid) and 18.3% (carbamazepine). The comparative between-batch CVs for the TDx varied between 2.0% (phenytoin) and 7.0% (valproic acid). Analysis of 209 patient samples containing carbamazepine, phenytoin, phenobarbitone, or valproic acid demonstrated significant correlation between the two analytical methods, with correlation coefficients of 0.9336, 0.9560, 0.9448, and 0.9618, with slopes of the regression lines of 0.9042, 0.8663, 1.1368, and 1.1244, respectively. It is concluded that both the TDx and OPUS instruments exhibit comparable performance for the analysis of carbamazepine, phenobarbitone, phenytoin, and valproic acid in patient samples. Moreover, the OPUS instrument, with its facilities of random assay access and statim analysis, may be useful in an outpatient setting in which a major consideration would be a rapid turnaround of patient assay results.

We report an interaction between lamotrigine (LTG), a new antiepileptic drug (AED), and carbamazepine (CBZ) and its primary metabolite CBZ-10,11-epoxide (CBZ-E) in 9 consecutive patients (5 male, 4 female, aged 19-31 years). After introduction of LTG (median daily dose 200 mg, range 100-300 mg) the mean serum CBZ-E concentration increased by 45% (P less than 0.01) and the CBZ-E/CBZ ratio increased by 19% (P less than 0.02). In 4 patients these changes were associated with clinical toxicity (dizziness, nausea, diplopia). The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.

Oxcarbazepine, a new drug with antineuralgic properties has been evaluated in a long-term follow-up of 6 patients (2 males, 4 females; aged 42-77 years; mean 61 years), previously reported on with trigeminal neuralgia. Daily oral oxcarbazepine dose correlated significantly with both total oxcarbazepine (r = 0.851) and 10-OH-carbazepine (r = 0.958) serum concentrations. Mean percent free oxcarbazepine and 10-OH-carbazepine was 41 and 61% respectively and there was no significant difference in binding between male and female patients. Free serum concentrations of oxcarbazepine and 10-OH-carbazepine correlated significantly with total serum oxcarbazepine and 10-OH-carbazepine respectively, indicating that binding capacity of both are essentially constant within the respective ranges of 0.2-11.4 mumol.l-1 and 20-150 mumol.l-1 observed in the present study.

Antipyrine half life and clearance was compared in four patients with classical idiopathic trigeminal neuralgia during carbamazepine (CBZ) or CBZ/phenytoin (PHT) and after substitution with oxcarbazepine (OXC) monotherapy. OXC is observed to be less of a hepatic enzyme inducer than CBZ or CBZ/PHT in combination, however induction by OXC may be dose related.

Denzimol, a new anticonvulsant drug, is currently undergoing clinical evaluation. In this paper we report its use in six patients who were also taking carbamazepine and two patients taking phenytoin. There was a striking elevation of serum carbamazepine, carbamazepine-10, 11 epoxide and phenytoin concentrations in all patients on the addition of denzimol therapy. The interaction with carbamazepine is greater in severity than any other reported to date and denzimol's interaction with both carbamazepine and phenytoin is likely to prove of major clinical significance.

Simultaneous steady-state serum total and free (non-protein-bound) concentrations of carbamazepine and carbamazepine-10,11-epoxide were measured in 68 patients under the age of 21 years with epilepsy (44 males, 24 females; mean age, 11.8 +/- 4.5 years). Thirty patients were maintained on monotherapy with carbamazepine. Mean serum total carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 7.0 +/- 2.4 mg/L (29.5 +/- 10.0 mumol/L) and 1.5 +/- 0.6 mg/L (5.9 +/- 2.6 mumol/L), respectively. Mean serum-free carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 1.3 +/- 0.5 mg/L (5.7 +/- 2.1 mumol/L) and 0.5 +/- 0.3 mg/L (2.2 +/- 1.1 mumol/L), respectively. Binding of carbamazepine and carbamazepine-10,11-epoxide was 81% +/- 3% and 62% +/- 10%, respectively. There was no significant difference in binding between male and female patients or those maintained on monotherapy and polytherapy. Age correlated significantly with carbamazepine binding but not with carbamazepine-10,11-epoxide binding. Free concentrations of carbamazepine and carbamazepine-10,11-epoxide correlated significantly with total carbamazepine and total carbamazepine-10,11-epoxide concentrations, respectively, indicating that the binding capacities of both carbamazepine and carbamazepine-10,11-epoxide are constant at serum total carbamazepine concentrations within the quoted therapeutic range.

Carbamazepine and carbamazepine-10,11-epoxide were separated by high-performance liquid chromatography (HPLC) with acetonitrile-water as mobile phase, and detection was effected by UV absorption at 215 nm with a total retention time of less than 10 min. Plasma samples were extracted with dichloromethane and 4 M sodium hydroxide, and 10-methoxy-carbamazepine was added as internal standard. Other commonly used anticonvulsant drugs present in plasma showed no significant interference. The within-batch coefficient of variation for carbamazepine was 4.9% and carbamazepine-10,11-epoxide 5.9%. Between-batch coefficients of variation were 3.7% and 5.3%, respectively. Mean recovery for carbamazepine was 100.2% and for carbamazepine-10,11-epoxide 100.6%. This HPLC method was compared with both an enzyme immunoassay procedure (EMIT) and a gas-liquid chromatographic (GLC) method. Correlation coefficient between HPLC/EMIT for carbamazepine was 0.983, HPLC/GLC carbamazepine 0.988 and HPLC/GLC carbamazepine-10,11-epoxide 0.981.

Various factors that may influence the simultaneous concentration of total and free carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) in serum of 68 children (mean age 11.8 +/- 4.5 years) with epilepsy were assessed. Separation of free and bound drug fractions was achieved by ultrafiltration, and CBZ and CBZ-E concentrations were determined using a sensitive high pressure liquid chromatographic technique. Thirty children were on CBZ monotherapy. Both total CBZ and CBZ-E serum concentrations correlated significantly with their respective free serum concentrations. CBZ was 81 +/- 3% and CBZ-E 63 +/- 9% bound. There was no correlation between the CBZ dose and either CBZ total or free serum concentrations. A statistically significant correlation was, however, observed between CBZ dose and simultaneous CBZ-E total and free concentrations. CBZ total and free concentrations correlated significantly with those of total CBZ-E. A significant negative correlation was observed between age and total (r = -0.49, p less than 0.01) and free (r = -0.43, p less than 0.025) CBZ-E/CBZ ratios. Concomitant drug therapy (phenytoin, phenobarbitone, and sodium valproate) significantly elevated CBZ-E/CBZ ratios.

Blood samples from patients on long-term sodium valproate (Epilim) therapy were analysed for valproic acid by two procedures, enzyme immunoassay (EMIT) and gas-liquid chromatography (GLC). A critical evaluation of the effects of anticoagulants added to specimens was performed in addition to studies on reagent specificity, accuracy, and precision. EMIT valproic acid reagent showed high specificity, and there was a good correlation between results obtained by EMIT and GLC over a wide range of concentrations. The accuracy and precision of EMIT assay was good over the therapeutic range of valproic acid. The presence of the anticoagulant EDTA or of fluoride/oxalate produced a bias towards high results for valproic acid as compared with those obtained from the analysis of serum.

Ninety children with epilepsy were treated with carbamazepine (CBZ) alone or with other anticonvulsant drugs. Side-effects were noted in 14 patients. When 25 patients treated with CBZ alone (group 1) were compared with 27 on CBZ and sodium valproate (group 2) and with 38 on CBZ and one or more other anticonvulsants (group 3), the incidence of side-effects was two in group 1 (of whom one patient had a toxic plasma level of CBZ), but 12 in groups 2 and 3 combined. In all but three of the 14 patients with side-effects, plasma levels of CBZ were within the 'therapeutic range'. A significant difference was found between the carbamazepine-10,11-epoxide (CBZ-10,11-EPOX) levels in plasma and CBZ-10,11-EPOX/CBZ ratio in patients with and without side-effects. For five patients on CBZ and other drugs, changes in treatment resulted in changes in side-effects, and also in CBZ-10,11-EPOX levels. Three of these patients showed an interaction between CBZ and sodium valproate, with a correlation between plasma CBZ-10,11-EPOX and side-effects when either drug was introduced or withdrawn, the plasma levels of CBZ itself and of sodium valproate being within the 'therapeutic range'.

A case report on a 13-year-old girl with idiopathic grand mal epilepsy who ingested 34 g carbamazepine (CBZ) and 80 mg clonazepam is presented. The patient survived but suffered severe temporary neurological toxicity characteristic of CBZ. CBZ was 79.6 +/- 2.8% bound to serum protein and carbamazepine-10,11-epoxide (CBZ-E) binding was essentially concentration dependent. CBZ and CBZ-E elimination half-lives were 26 and 16.5 h respectively. An inhibitory metabolic interaction with the co-ingested clonazepam is suggested.

A method of measuring carbamazepine-10,11-epoxide (CBZ-10,11-EPOX) has been developed and used to monitor plasma concentrations in children suffering from various forms of epilepsy. Children stabilised on standard doses of CBZ alone showed a ratio of CBZ-10,11-EPOX/CBZ of 18.92 +/- 8.08, expressed as a percentage of the CBZ concentration, while those on multiple-drug therapy (with the exception of benzodiazepines and phenobarbitone) showed both increased values of CBZ-10,11-EPOX/CBZ ratio and increased absolute concentrations of CBZ-10,11-EPOX in plasma. These changes correlated with clinical side-effects which could not be attributed to CBZ itself or to the other drugs administered concurrently.