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The new antiepileptic drug vigabatrin acts by preventing degradation of the inhibitory neurotransmitter GABA (gammaaminobutyric acid). This appears to decrease propagation of abnormal hypersynchronous discharges, thus reducing seizure activity. In an open study in 46 patients with intractable epilepsy, supplementary therapy with vigabatrin reduced seizure by at least 50% in 15 patients. Three patients became seizure-free. The best effect of vigabatrin is seen in patients with partial epilepsy. Tiredness and irritability were the most frequently reported side effects, but these were usually mild and transient.

Therapeutic drug monitoring includes measurement of serum concentrations of drugs when this is possible and appropriate. A therapeutic range is defined for populations where the serum levels represent an optimal relationship between clinical effects and side effects for most of the individuals in the population. Compared with the rest of the population, some individuals are atypical, both with respect to response to and elimination of drugs. Therapeutic drug monitoring makes individualization of dosages in these individuals easier, but often requires extra effort. Compilation of serum level measurements for different drugs for a period of six months showed that the tailoring of digitoxin, carbamazepine, lithium and phenobarbital is as close to optimal as can be expected for a population. For amitriptyline, digoxin and theophylline, a considerable increase in clinical effect within a population of users could probably be achieved by bringing more individual serum levels from the subtherapeutic into the therapeutic range. Nor does the therapeutic potential of phenytoin, nortriptyline and valproate seem to be fully utilized.

An increased risk of seizures during and immediately after labour has been observed in epileptic women, and it is recognized that serum levels of antiepileptic drugs may decrease in pregnancy. Several studies have suggested that total valproate levels fall, but that free fractions increase during pregnancy. Recent findings suggest that the actual metabolism of valproate is not altered by pregnancy and that the changes of the plasma clearance are due primarily to decreased protein binding. The levels of free drug will not change significantly as pregnancy advances. However, dose reduction after delivery may be necessary to avoid toxicity. Valproate and its metabolites undergo placental transfer. In the foetus the plasma level of valproate and the protein binding are higher than in maternal plasma, and the half-life of valproate following placental transfer is considerably longer than in adults. Only small amounts of valproate appear in breast milk and those are not likely to cause any problems. During pregnancy and the first month after delivery preferably both total and free valproate serum levels should be closely monitored to determine the lowest effective dose.

Different parameters of antiepileptic drug (AED) treatment have been shown to affect cognitive function. The drug, dose, and duration of treatment have been studied. The present study assessed cognitive function in relation to time-of-day variation in serum carbamazepine (CBZ) concentration in epileptic patients treated with monotherapy. We studied 10 males and 12 females with a mean age of 36 years and a mean duration of CBZ-therapy of 4.4 years. Patients had been seizure-free for at least 1 month and took two daily CBZ doses. The test battery included tests of motor speed, reaction time, attention, and memory. In the experimental design, the subjects were tested twice at times close to expected daily maximum and minimum serum CBZ concentration. They were studied in two balanced blocks (block 1 tested at 8 a.m. and noon, block 2 tested at noon and 8 p.m.). Blood samples were collected every 2 hr from 8 a.m. to 8 p.m. The subjects showed significant differences in serum CBZ concentration between testing times, with suggested maximum concentration between 10 a.m. and noon. The test battery showed no consistent differences between performance at times of high versus low serum concentration. A supplementary analysis of correlations between mean performance level on cognitive tests and variables related to CBZ treatment did not show consistent trends.

Drug assays play an important role in the control of antiepileptic treatment because the relationship between the serum concentration of an active drug and its therapeutic effects and side-effects is closer than between dose and effect. Bioavailability, protein binding and drug elimination are subject to inter- and intraindividual variations. However, it is important to remember that the optimal therapeutic ranges reported for serum levels are only a guideline to drug therapy. It is the patient who must be treated and not the serum level.

Twenty-one adult in-patients (11 women, 10 men, aged 18-39 years) with uncontrolled epilepsy participated in a 4-week intensive physical training program, exercising for at least 45 min three times a day, 6 days a week, at an intensity of minimum 60% of maximum oxygen uptake (maximum VO2). The program induced a considerable increase in maximum VO2 (mean 19%). Beneficial psychological and social effects were also recorded. The average seizure frequency during the 4-week exercise period was compared with 2 preexercise and 2 postexercise weeks. There was no significant difference, but there was considerable variation among patients. Only six patients had seizures during exercise. The occurrence had no relation to seizure type, mode of activity, or pulse rate. We conclude that physical activity does not represent an important seizure-inducing factor in general, and that in most people with epilepsy physical training appears to have a favorable influence. The exact mechanism behind this influence is not known, but physiologic as well as psychological and social effects may be of importance. Physical training did not change the serum levels of the antiepileptic drugs to a clinically important degree.

The serum concentration achieved and maintained following the administration of a fixed drug dosage is a direct consequence of the interactions of a wide variety of interrelated processes, including drug absorption, distribution, metabolism, and excretion, and the physiological status of the patient. These interrelationships are reviewed with specific reference to the major anti-epileptic drugs, phenobarbitone, phenytoin, sodium valproate, and carbamazepine, as well as a new first-line antiepileptic, oxcarbazepine.Both older drugs, such as phenobarbitone and phenytoin, and newer drugs, such as carbamazepine (CBZ) and sodium valproate, have been studied extensively over the past years giving valuable information for drug treatment. An important feature of oxcarbazepine (OXC) , which was developed through minimal changes in the structure of CBZ in order to improve on the tolerability of CBZ without sacrificing efficacy, is that its metabolites do not include the 11-epoxide which has been implicated in the side-effects of CBZ. In man, OXC is metabolized to a monohydroxy derivative which has independent anti-epileptic properties. OXC seems to lack several disadavantageous pharmacokinetic properties common to other major anti-epileptic drugs. OXC does not influence its own metabolism after repeated administration, in contrast to the auto-induction displayed by CBZ. The metabolism of OXC is not influenced by anti-epileptic co-medication and does not influence the kinetics of other anti-epileptic drugs - or if it does, then to a lesser extent than CBZ.

Plain tablets of sodium valproate (VPA), a useful antiepileptic drug, are bitter tasting and produce gastric irritation which leads to poor patient compliance. We have studied the steady state serum levels of VPA which can be produced in epileptic patients before and after a 1 week treatment with a plain tablet (Deprakine) versus an enteric coated tablet (Orfiril). The latter drug produced in most patients a higher drug fasting blood level than the uncoated preparation (22%). The enteric coated tablets appeared also better tolerated.

Results of clinical and pharmacokinetic observations on sodium valproate (VPA) are reported from a long-term study in 100 children with epilepsy. VPA is the drug of choice in patients with absences. VPA may preferably be chosen as the first drug in patients with atonic seizures partly because all treatment of these seizures is uncertain, and the effect of VPA may be striking, without side effects. When starting with VPA the great problem of drug interactions is avoided. Treating patients with intractable epilepsy has shown that VPA may be effective in all seizure types regardless of the EEG-findings. However, generalized paroxysms of spike and wave complexes in the EEG are a good prognostic sign especially when fairly regular. Side effects are few when using enteric coated tablets, but toxic effects may be serious. Control schemes of blood and liver functions are necessary. Drug fasting serum level monitoring is mandatory, especially when VPA is given in combination with other anti-epileptic drugs as interactions with these are pronounced. Optimal clinical effect is usually seen on serum levels between 300 and 600 microgram mol/l, which may be obtained by giving 10-20 mg/kg daily assuming that the patient is receiving VPA monotherapy, which should always be aimed at. Comedication may have to be withdrawn to obtain therapeutic serum levels of VPA due to drug interactions.

A 28-year-old man with regularly occurring clusters of complex partial seizures was studied over a total of 224 days. His seizure periods lasted 2-4 days and occurred at intervals of 5-6 weeks. Several parameters were studied. The most striking finding was an increase in the serum concentration of thyroxine prior to and during the seizure periods. The concentrations of urine catecholamines and serum cortisol also varied with the seizure periods, but these hormones increased after the seizure periods had begun. To determine if there is a general 4-6-week rhythm in thyroid hormone concentrations, 12 weekly blood samples from 10 healthy male students were analyzed. No rhythmicity was found.

Serum and CSF samples of patients receiving chronic carbamazepine treatment were analysed. Daily fluctuations in serum levels of carbamazepine and carbamazepine-10,11-epoxide did not appear to be related to the dosage schedule, but some patients tended to have lower fluctuations when the carbamazepine was given more frequently. The epoxide/carbamazepine serum ratios varied greatly from patient to patient, and also fluctuated during the day for the same patient. Carbamazepine and carbamazepine-10,11-epoxide were present in CSF in concentrations ranging from 19 to 34% and 26 to 71% of the serum concentrations, respectively. There was a significant relationship between the free fraction of both drugs evaluated in vivo and the CSF/serum ratios. The need for a careful evaluation of the possible clinical effect of the epoxide is stressed.

Serum level monitoring of antiepileptic drugs is important for an optimal drug therapy since relationships between serum levels and therapeutic and toxic effects have been clearly established for several drugs. Routine serum level monitoring based on pharmacokinetic and clinical knowledge has improved the treatment of epileptic patients. For routine determination of antiepileptic drugs, homogenous enzyme immunoassays offer several advantages over more complex techniques such as GLC and HPLC. Because of the speed of the analysis and the small sample volume, EMIT is the method of choice in many laboratories. A 50-microliter sample is sufficient for a single determination of up to five drugs. To ensure reliable results, quality control schemes are necessary regardless of the analytical technique utilized for drug quantitation. Routine monitoring of serum levels is especially important since drug bioavailability, as well as the rate of drug metabolism and excretion, varies widely among patients. Serum levels are also influenced by comedication. Changes in protein binding may also be of clinical importance under special circumstances. Active metabolites may contribute to the clinical effect of a drug. Correct dose frequency and standardized blood sampling time, preferably before the first morning drug dose, are also important factors for establishing optimal therapeutic regimens for a given patient. The serum levels of antiepileptic drugs should be determined when drug therapy is initiated, after dosage adjustments, in case of therapy failure, after addition of drugs which may cause drug interactions, when clinical signs of side effects or drug intoxication occur, and as a routine monitoring for patient compliance. Serum levels should be monitored if any change occurs in a patient's normal pharmacological state.

Patients on long-term treatment with either of the stereochemically related antiepileptic drugs phenytoin (DPH) or carbamazepine (CBZ) had similar changes in serum thyroid hormone concentrations. T4, FT4, FT4 index, T3, FT3, FT3 index and rT3 were reduced, whereas T3U and TSH were not significantly different from the reference group levels. Long-term phenobarbitone treatment had no convincing effect on the investigated parameters when used alone, but possibly potentiated the effect of CBZ. In patients starting on CBZ, T4 fell to a stable 70% of the basal level after 1--2 weeks. T3 decreased transitorily to 85% of the basal level. TSH showed a complementary but somewhat delayed transitory increase. T3U and TBG did not change significantly. The effect of CBZ and DPH can be explained by interference with thyroid hormone binding to TBG combined with enzyme-induced increased metabolic clearance rate of thyroid hormones without homeostatic maintenance of premedication levels of FT4 and FT3. We suggest that the regulated factor maintaining euthyroidism in these patients is the total quantity of thyroid hormones being degraded in the tissues per unit time. We conclude that serum concentrations of FT4 and FT3 do not reflect thyroid status adequately under all circumstances.

The concentrations of IgA, IgG and IgM were determined in sera of 16 patients, all of whom had partial epilepsy and had received CBZ as the only drug since the beginning of therapy. Fifty-three healthy subjects served as controls. Serum concentrations of IgA and IgG were significantly higher in patients than in controls (IgA: P = 0.05; IgG: P = 0.01). The concentration of IgM was not significantly different from that of the controls (P = 0.1). The IgG serum levels in the controls were lower with increasing age. Furthermore, IgG serum levels were higher with increasing CBZ concentrations.

Hypothyroidism induced by anti-epileptic drug treatment gave rise to thyroid function test studies in patients treated with carbamazepine (CBZ) only. In 42 patients on long-term CBZ treatment thyroxine (T4), free T4-index (FT4I), and triiodothyronine (T3) concentrations in serum were significantly lower than in controls, while triiodothyronine uptake (T3U) and thyrotropin (TSH) concentrations did not differ between patients and controls. In 12 patients starting on CBZ, means T4, calculated FT4 and thyroxine binding globulin (TBG) were 1-5 months later reduced compared to the initial levels. Thus, CBZ reduced thyroid hormones, TBG and FT4I. A CBZ-induced increase in conversion and metabolism of the thyroid hormones could explain this effect. The normal T3U values and decreased concentrations of TBG make a competitive CBZ binding to TBG less probable. Although the thyroid hormones levels were found lowered in the patients, all remained clinically euthyroid during the study.

A rapid gas chromatographic method for determination of sodium valproic acid (di-n-propylacetate, DPA) is described. A new sample can be injected every third min, and the reproducibility, in terms of the coefficient of variation, is better than 3%. The method has been used to study clinical pharmacokinetics of DPA in patients with epilepsy during long-term treatment. A poor correlation between daily dose (mg/kg) of DPA and steady state serum levels, attained within few days, was observed. A fixed sampling time in the individual patient, preferably before ingestion of the morning dose, is of great importance for DPA due to extended fluctuations of the serum levels during the day. Most patients had DPA serum levels in the order of 50 microng/ml. No constant relationship was found between increase of the dose and the corresponding increase of the serum levels. Interactions of clinical importance was observed between DPA and other antiepileptic drugs, as addition of DPA resulted in elevated serum levels of diphenylhydantoin and phenobarbital. Carbamazepine levels were unaltered. After withdrawal of DPA the half-life was about 14 h in adult patients. DPA levels in CSF were in the order of 10% of the corresponding serum levels.

The influence of clonazepam on steady-state serum levels of diphenylhydantoin, phenobarbital and carbamazepine was studied in 22 patients with epilepsy receiving one or two of these drugs. Clonazepam was given in slowly increasing doses for 2 weeks until a maximum dose of 4-6 mg per day was reached; thereafter the dose was kept constant. The serum levels of diphenylhydantoin, phenobarbital and carbamazepine were determined once a week for at least 6 weeks. During clonazepam medication in ordinary doses the serum levels of the drugs in question were unaltered. Thus, it is unlikely that the antiepileptic effect of clonazepam in these patients even partly may be due to increased serum levels of these other drugs mentioned.

Carbamazepine (CBZ) was given as the only drug to 62 epileptic patients with mainly simple and complex partial seizures. Twenty-four of the patients were given CBZ as the only drug from the beginning of therapy, while 38 patients had formerly received other antiepileptic drugs. Serum concentrations of CBZ and CBZ-10,11-epoxide were determined by enzyme immunoassay and gas chromatography, respectively, in fasting morning blood specimens. Twenty of the 24 patients given CBZ from the beginning were seizure-free at follow-up 7-48 months later. These patients had a mean daily dose of CBZ of 7.5 (+/- 0.56) mg/kg and mean CBZ and epoxide serum concentrations of 23.4 (+/- 1.16) and 2.4 (+/- 0.20) mumoles/liter, respectively. The corresponding values for 25 of the 38 patients previously treated with other antiepileptic drugs were 10.3 +/- 0.66 mg/kg and 29.4 +/- 1.60 and 3.1 +/- 0.18 mumoles/liter. The follow-up in these patients was 11-58 months. Thirteen patients had poor seizure control, although they had serum CBZ and epoxide concentrations within the ranges giving seizure control in the rest of the patients. The concentrations of the epoxide in serum were significantly correlated to the concentrations of CBZ (r = 0.63, p < 0.01). The therapeutic range, 13-51 mumoles/liter, indicates great interindividual differences in optimal levels of CBZ. Accordingly, individually tailored drug regimens are necessary to achieve optimal therapeutic effects with CBZ.