Antiepileptic Drug Concentrations Research Articles

The Role of Therapeutic Drug Monitoring in Improving the Cost Effectiveness of Anticonvulsant Therapy

When monitoring of the plasma concentrations of anticonvulsant drugs first came into use 25 years ago, it appeared to have a major impact on improving the effectiveness and safety of anticonvulsant therapy. However, as time has passed, prescribers have absorbed many of the lessons to be learned from the monitoring, and now apply this knowledge without necessarily monitoring plasma anticonvulsant concentrations as frequently as in the past. Therefore, the effect of the drug concentration monitoring on the cost effectiveness of anticonvulsant therapy is probably not as significant now as it originally was. In theory, drug concentration monitoring is often unlikely to decrease the cost of contemporary anticonvulsant drug therapy, but it may enhance the efficacy of the therapy. Thus, monitoring may reveal unrecognised under- or overdosage, detect failure of compliance or drug-drug interactions, or indicate when there is little point in persisting with a particular anticonvulsant drug. Despite a good deal of anecdotal testimony, surprisingly little has been published demonstrating the benefits of anticonvulsant therapeutic drug monitoring in epileptic populations. However, one study did show better rates of seizure control rates in patients monitored in the first 6 months of their epileptic disorder; but not if the monitoring began later than this.(ABSTRACT TRUNCATED AT 250 WORDS)

Tiagabine pharmacology in profile.

Tiagabine (TGB) hydrochloride, a nipecotic acid derivative linked to a lipophilic anchor, potently and specifically inhibits uptake of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) into astrocytes and neurons. With microdialysis, TGB has been shown to increase extracellular overflow of GABA in the midbrain of awake rats. TGB administration prolongs neuronal depolarization induced by iontophoretically applied GABA in hippocampal slices. TGB is effective in a wide range of seizure models, including pentylenetetrazol-induced, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)-induced tonic, amygdala-kindled and picrotoxin-induced convulsions, and maximal electroshock seizures in rodents. In humans, TGB absorption is rapid and complete. It is metabolized in the liver, largely by isoform 3A of the cytochrome P450 family of enzymes. The process of elimination is linear, with a half-life of 5-8 h. TGB does not induce or inhibit metabolic processes, although it provides a target for enzyme inducers that can lower its elimination half-life to 2-3 h. Accordingly, TGB does not alter the concentrations of other antiepileptic drugs (AEDs), with the possible exception of a small decrease in valproate levels. A controlled-release formulation of TGB would offset any potential clinical disadvantage of the short elimination half-life, particularly in patients receiving concurrent treatment with enzyme-induced AEDs.

Anticonvulsant therapy in the elderly—A need for placebo controlled trials

Epileptic seizures are common in the elderly, yet data concerning the long-term clinical course and apparent impact of anticonvulsant therapy are scant. We studied 73 consecutive elderly patients with a diagnosis of seizures [remote symptomatic (52%), acute symptomatic (23%), progressive symptomatic (10%), cryptogenic (15%)] during a median period of clinical review of 33 (range 3-72) months. Sixty-seven patients received anticonvulsant drugs, 38 phenytoin (PHT), 21 carbamazepine (CBZ), 6 sodium valproate (VPA) and 2 phenobarbitone. Six patients were untreated with drugs and three of these had no further seizures over a median review period of 26 months. Forty-one (61%) treated patients remained seizure free and a further nine patients suffered less than three fits per year. Seventeen patients had poorer control (three to five seizures per year in six patients and more than five seizures per year in eleven patients). Mean daily dosage of anticonvulsants (PHT 248 mg, CBZ 320 mg, VPA 571 mg) and serum concentrations were modest. Anticonvulsant side effects were reported by 27% of all treated patients (22% of those who were seizure free). Both adverse effects and satisfactory seizure control were associated in the majority of patients with serum anticonvulsant concentrations at the lower limit or below recommended therapeutic ranges utilised in the young. This study suggests that placebo controlled studies are warranted to appraise the extent to which anticonvulsant drugs modify a generally favourable prognosis for seizure disorders in the elderly and to adequately define the benefit-risk ratio of such drugs.

The effect of age on pharmacokinetics of antiepileptic drugs.

Management of epilepsy in the elderly requires understanding of the unique biochemical and pharmacologic characteristics of this patient population. Accurate assessment of seizures and identification of epilepsy syndromes, thorough neurologic assessment to define etiology, and comprehensive evaluation of the patient's health and living situation are necessary for informed management decisions. Challenges to treatment include concomitant diseases, polypharmacy with accompanying drug interactions, and changes in physiology, such as changes in renal clearance and hepatic function than alter drug absorption, protein binding, metabolism, and elimination. Elderly patients with declining intellectual function, motor impairment, or altered sensory function may be especially susceptible to dose-related CNS side effects of antiepileptic drugs (AEDs). Drugs prescribed for concomitant illnesses such as hypertension, cardiovascular disease, infections, behavioral problems, and gastrointestinal disturbances may alter absorption, distribution, and metabolism of AEDs, with an adverse impact on efficacy and increased occurrence of adverse effects. The AEDs may induce metabolism of other drugs, resulting in decline in target response. Addition of an AED to an elderly patient's medical regimen requires careful review of all prescribed drugs. Optimal care of elderly patients with epilepsy includes use of free drug levels to monitor AED concentrations, careful dose selection, and sensitivity to the social problems that may occur in this population.

The Management of Epilepsy in the 1990s

The pharmacological treatment of epilepsy has made considerable progress during the last decade, due to improved knowledge of the clinical pharmacology of individual drugs, acquisition of new information on the factors affecting response and need for drug treatment, and development of promising new agents. Once a clinical diagnosis of epilepsy has been made (which generally requires the occurrence of more than one seizure), treatment should be started with a single drug selected on the basis of seizure type and tolerability profile. Although there are important regional differences in prescribing patterns and individual circumstances may dictate alternative choices, carbamazepine is generally regarded as the preferred treatment for partial seizures (with or without secondary generalisation) while valproic acid (sodium valproate) is usually the first choice in most forms of generalised epilepsies. To achieve therapeutic success, the daily dosage must be tailored to meet individual needs, and there is suggestive evidence that in some patients the dosage prescribed initially may be unnecessarily large. Plasma antiepileptic drug concentrations may aid in the individualization of dosage, but should not be regarded as a substitute for careful monitoring of clinical response. Although overall about 70% of patients can be completely controlled, response rate is influenced by a number of factors, the most important of which are seizure type and syndromic form. The importance of a correct syndromic classification for rational drug selection has been poorly assessed and represents a major area for future research. Patients who do not respond to the highest tolerated dose of the initially prescribed drug may be switched to monotherapy with an alternative agent or may be given add-on treatment with a second drug. Appropriate prospective trials are required to assess the merits of either strategy. If add-on therapy is selected and the patient becomes seizure free, it may be possible to discontinue the drug prescribed initially and reinstitute monotherapy. Only a minority of patients are likely to require multiple drug therapy, and it remains to be established whether specific drug combinations are more effective than others. Until further information becomes available, the new agents should be reserved for patients failing to respond to the conventional treatments of first choice. Patients whose seizures cannot be controlled by available drugs should be reassessed, and polytherapy should be maintained only when there is clear evidence that benefits outweigh possible adverse effects. In many patients who have been seizure free for at least 2 years it may be possible to gradually discontinue all medications.(ABSTRACT TRUNCATED AT 400 WORDS)

Predicting Unbound Phenytoin Concentrations In Patients Receiving Valproic Acid: A Comparison of Two Prediction Methods

To compare the predictive performance of 2 equations that estimate unbound (free) phenytoin plasma concentrations when valproic acid (VPA) and phenytoin are administered concurrently. Eighty-eight adults receiving VPA and phenytoin concurrently were included in the study. Steady-state plasma concentration measurements of total phenytoin, total VPA, and unbound phenytoin were collected prospectively in the inpatient group (group 1) and retrospectively in the outpatient group (group 2). Using the equations developed by Haidukewych and May, unbound phenytoin concentrations were calculated. The mean predicted unbound phenytoin concentrations then were compared with mean actual unbound phenytoin concentrations measured in the laboratory. Identical assays were performed to measure unbound phenytoin, total phenytoin, and VPA from each patient group. Antiepileptic drug concentration measurements were collected from 43 inpatients (mean age 34.8 y) from the epilepsy unit at Abbott Northwestern Hospital and 45 outpatients (mean age 37.3 y) at the MINCEP Epilepsy Care clinic, Minneapolis, MN. Mean prediction error (MPE) and mean squared error (MSE) were calculated to determine which equation was the least biased and most precise in predicting unbound phenytoin when total VPA and phenytoin concentrations are known. Linear regression of predicted unbound phenytoin on measured unbound phenytoin values determined the correlation coefficients (r). A paired Student's t-test also was performed comparing mean predicted unbound phenytoin concentration with mean actual unbound phenytoin concentrations in both groups. The MPE from May's equation was -0.49 and -0.45 for groups 1 and 2, respectively; using the Haidukewych equation, MPE was -0.02 and 0.08 for groups 1 and 2, respectively. The MSE using May's equation was 0.34 for both groups. Using the Haidukewych equation, group 1 MSE was 0.07, and for group 2, 0.12. Correlation coefficients were more than 0.91 (p < 0.001) from each equation in both patient groups. In group 1, mean actual unbound phenytoin concentration was 2.02 micrograms/mL; May's equation predicted 1.52 micrograms/mL (p < 0.001) and the Haidukewych equation predicted 2.00 micrograms/mL (p = 0.64). In group 2, mean actual unbound phenytoin concentration was 2.10 micrograms/mL; May's equation predicted 1.65 micrograms/mL (p < 0.001) and the Haidukewych equation predicted 2.18 micrograms/mL (p = 0.11). Haidukewych's equation predicts unbound phenytoin concentrations with the least bias and most precision with statistical significance. May's equation consistently underpredicted unbound phenytoin concentrations. Because unbound phenytoin fraction is not constant (and usually more than the expected 10%) in patients comedicated with VPA, unbound phenytoin concentrations cannot be predicted even though total VPA and phenytoin concentrations are known. If unbound phenytoin concentrations cannot be readily measured, Haidukewych's equation is a reliable predictor of unbound phenytoin concentrations.

Antiepileptic Agents and Birth Defects

An association exists between maternal use of antiepileptic drugs (AEDs) during pregnancy and birth defects in offspring. The overall malformation rate is 11.1% in offspring of AED-treated epileptic mothers, while it is 5.7% in the offspring of untreated epileptic mothers and 4.8% in those of the general population. Cardiovascular defects, facial cleftings and skeletal anomalies are the most frequently occurring AED-associated malformations. No firm patterns of specific AEDs inducing particular birth defects have been established. Nevertheless, neural tube defects may be specific malformations in infants exposed to both valproic acid (sodium valproate) and/or carbamazepine. Several minor anomalies are influenced by genetic factors. From prospective studies a number of primary risk factors for increased incidences of congenital malformations in the offspring of epileptic mothers receiving AEDs have been identified. These include high drug dosage, high serum drug concentration, the use of AEDs with high teratogenicity potency [primidone > valproic acid > phenytoin > carbamazepine > phenobarbital (phenobarbitone)] and AED polypharmacy (especially combinations of valproic acid and carbamazepine, and phenytoin and/or carbamazepine with or without barbiturates). The mechanism of teratogenicity of AEDs is still being investigated, but it is postulated that epoxide intermediates and other toxic metabolites of AEDs might be involved. In addition, the folate deficiency and impaired folate metabolism caused by AEDs may contribute to the teratogenicity of these drugs. To prevent birth defects, the use of the lowest effective AED dosage and a change from polypharmacy to monotherapy are recommended before conception. A decrease in serum AED concentrations during pregnancy does not in itself justify an increase in drug dosage. The high risk of neural tube defects in offspring exposed to valproic acid (or carbamazepine) warrants prenatal examination in pregnant women receiving this drug, such as ultrasound and amniotic fluid α-fetoprotein investigations. To reduce the risk of this malformation, replacement of conventional formulations of valproic acid with controlled release formulations and the use of folate supplementation are recommended.

Developmental Principles of Antiepileptic Drug Therapy

Antiepileptic drug therapy in children can be challenging because seizure semiology and drug disposition change dramatically over time. Close monitoring of drug clearance is required in early life because of the rapid ontogenesis of drug-eliminating organs. Large variations in serum peak and trough antiepileptic drug concentrations increase the risk for both adverse drug effects and unsatisfactory seizure control. Antiepileptic drug adverse effects also differ, probably relative to different receptor sensitivities in children. Failure to appreciate the developmental differences between children and adults can result in medication noncompliance, breakthrough seizures, and unacceptable adverse effects.

Plasma Antiepileptic Drug Monitoring in a Neurological Practice

Rates for being free of all epileptic seizures for at least 1 year and for ceasing therapy after 3-5 years of full seizure control were similar in 548 treated epileptic patients referred from 1962 to 1970, during which period plasma antiepileptic drug concentration monitoring became available (32.7 and 17.0%, respectively), in 960 patients referred from 1971 to 1979, when such monitoring was used increasingly (29.6 and 14.9%, respectively), and in 348 patients referred from 1980 to 1989, when this monitoring was widely available (30.5 and 10.1%, respectively). However, monitoring was associated with higher rates of full seizure control in patients seen within 6 months of their first seizure, even when patients with only a solitary seizure were excluded. Possibly, monitoring then helped achieve early complete suppression of not yet established seizure processes, but had less effect on already entrenched seizure mechanisms. Plotting cumulative percentages of patients with fully controlled seizures versus plasma antiepileptic drug concentrations yielded data that were broadly in keeping with conventional 'therapeutic' ranges for phenytoin, carbamazepine, phenobarbital, and ethosuximide monotherapy. With a given plasma phenobarbital (but not phenytoin or carbamazepine) concentration, rates of full seizure control were appreciably higher for generalized onset than for partial onset seizures. Use of a second antiepileptic drug was associated with improved full seizure control in both generalized onset and partial onset seizures, which had not been controlled by monotherapy; adding a third drug yielded little further benefit.

Saliva Versus Blood Sampling for Therapeutic Drug Monitoring in Children

The objective of this study was to conduct an assessment of patient and parental preferences and an economic analysis of hospital costs in sampling blood and saliva for therapeutic drug monitoring (TDM). Costs and preferences were evaluated in the course of a study, which compared anticonvulsant concentrations in blood routinely drawn for therapeutic monitoring and in saliva in infants and children attending a pediatric neurology clinic. Parents of 84.8% of children, and half of the children, indicated a preference for saliva sampling over venous blood drawing. Children who had been on medications that required therapeutic monitoring for < 2 years were more likely to prefer saliva sampling as compared to those who were under treatment for > or = 2 years. Computation, based upon a basic assumption that a registered nurse obtained blood and a medical technician or a registered nurse assistant sampled saliva, indicated that for every 1,000 cases of changing from blood to saliva sampling, total cost savings would amount to $1,930 for cooperative children and $1,660 for infants and uncooperative children. This saving is equivalent to approximately 100 h of a registered nurse's initial salary. The important contributions to the differential cost were derived from the requirements for more highly trained individuals to take the blood sample and from the doubling time required for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of anticonvulsant drugs on GABA-stimulated chloride uptake.

Eight anticonvulsant drugs-including clonazepam, diazepam and phenobarbital-were tested for their effects on GABA-stimulated chloride uptake in rat cerebral cortical microsacs (unfiltered synaptoneurosomes). "Mid" and "high" therapeutic concentrations were screened, and, if significant enhancement was found, full concentration-response tests were done. In the initial screens, enhancement of GABA-stimulated uptake was found only with phenobarbital, clonazepam and diazepam. In subsequent concentration-response tests, the effects of phenobarbital were found to occur throughout the range of normal, anticonvulsant concentrations, whereas the effects of clonazepam and diazepam were observed only above the concentrations normally used for the chronic control of seizures or anxiety. These data suggest that phenobarbital's anticonvulsant effects are mediated via the GABAA receptor complex, but that the low-dose effects of the benzodiazepines may be mediated via some other mechanism.

Pharmacodynamic interactions between phenytoin and valproate: individual and combined antiepileptic and neurotoxic actions in mice.

Although the current trend is to use monotherapy in the treatment of epilepsy, combination therapy is still employed in patients who have failed to respond to monotherapy. There is little clinical or experimental documentation of evidence against or in favor of anticonvulsant combination therapy. In this context, anticonvulsant and neurotoxic pharmacodynamic interactions between phenytoin (PHT) and valproate (VPA) were assessed in an experimental model in mice. All results were expressed in terms of brain drug concentrations for eliminating any pharmacokinetic interaction from the analysis. Both the median neurotoxic and the median anticonvulsant brain concentrations were determined for each drug used alone and for the combination. The interaction for the combination of PHT and VPA was shown to be supraadditive for the anticonvulsant activity, indicating an antiepileptic potentiation, whereas neurotoxicity was simply additive. These results suggest a potential benefit in terms of overall efficacy versus toxicity for the combination of PHT and VPA, as compared with PHT or VPA used alone.

Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin.

Seizure control and plasma concentrations of antiepileptic drugs (AEDs) were determined in a prospective, population-based study of 93 pregnancies (cases) of 70 patients with epilepsy. Seventy-seven cases were treated with monotherapy, which in 70 cases consisted of carbamazepine (CBZ) or phenytoin (PHT). Dosage was kept constant unless poor seizure control prompted an increase. Plasma concentrations were determined at monthly intervals throughout pregnancy and compared with baseline levels obtained at least 10 weeks postpartum. Both free and total CBZ and PHT concentrations were analyzed. Seizure frequency during pregnancy for the group as a whole was not different as compared with the 9 pregestational months and was unaltered or improved in 85% of cases. Total CBZ concentration was slightly lower during the third trimester as compared with baseline, whereas free concentration was unchanged. In contrast, PHT levels decreased steadily as pregnancy progressed. Total plasma concentration was 39% of baseline during the third trimester, whereas free PHT concentration decreased far less, being 82% of baseline level during the third trimester. No clear-cut relation could be demonstrated between seizure control and plasma concentrations, which may be explained by the limited changes in free AED concentrations and the small number of cases with an increased seizure frequency. Our results indicate that total plasma concentrations may be misleading and that monitoring of free concentrations, in particular of PHT concentrations, may be advantageous during pregnancy.

Critical Issues in the Treatment of Epilepsy

Classification of seizure types and evaluation and treatment of seizure disorders are discussed. Once the diagnosis of a seizure is made, the seizure type must be identified; this will help in determining the treatment. In partial seizures, the electrical discharge occurs focally, while generalized seizures involve both cerebral hemispheres simultaneously. Magnetic resonance imaging is the preferred test in the evaluation of patients with seizures, although computed tomography and electroencephalography can also be helpful. Selection of an antiepileptic drug (AED) is based on efficacy, toxicity, and, to a lesser degree, cost. Adverse reactions occur in up to 50% of patients. First-line AEDs include carbamazepine, ethosuximide, phenobarbital, primidone, phenytoin, and valproic acid. Serum AED concentrations can be helpful in managing patients with epilepsy. The serum concentrations required to control seizures or resulting in toxicity may vary among patients. Most seizures are manageable with oral AEDs. Medications of choice in status epilepticus include diazepam, lorazepam, phenytoin, and phenobarbital. The key to treating epilepsy is correct diagnosis of the seizure type and, when possible, the type of epilepsy. Most patients with epilepsy respond to one of the first-line AEDs; second-line agents may be useful in patients who do not respond to one or a combination of the first-line agents.

Lamotrigine Clinical Pharmacokinetics

Lamotrigine is a new antiepileptic agent chemically unrelated to any established drugs in use. The drug can be estimated in biological fluids by high performance liquid chromatography and immunoassays. It is rapidly absorbed, reaching peak concentrations within about 3 hours postdose. The bioavailability of the oral formulation is about 98%. The area under the plasma concentration-time curve indicates dose-linear pharmacokinetics. The degree of plasma protein binding is 56%. Saliva concentrations are 46% of the plasma concentration. The concentration of lamotrigine in the brain is similar to the total concentration in the plasma. Lamotrigine exhibits first-order linear kinetics during long term administration. 43 to 87% of a dose is recovered in the urine, predominantly as glucuronide metabolites. Mean half-lives of lamotrigine in healthy volunteers (single and multiple doses) as well as in epileptic patients receiving lamotrigine monotherapy range from 22.8 to 37.4 hours. Enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital (phenobarbitone) or carbamazepine reduce the half-life of lamotrigine (to mean values of 13.5 to 15 hours), whereas valproic acid increases the half-life of the drug (to mean values of 48.3 to 59 hours). Lamotrigine itself does not influence the plasma concentrations of concomitant antiepileptic drugs, except for causing an increase in concentrations of carbamazepine-10,11-epoxide, the main metabolite of carbamazepine. Other observations indicate that the interaction of carbamazepine and lamotrigine may be primarily pharmacodynamic rather than pharmacokinetic. Usual dosages of lamotrigine range from 50 to 400 mg/day depending on an enzyme-inducing or -inhibiting comedication. Therapeutic plasma concentrations of the drug are not known, but a putative therapeutic range of 1 to 4 mg/L has been proposed. Some patients have tolerated concentrations > 10 mg/L with benefit and without clinical toxicity. The value of measuring the concentrations of lamotrigine in helping to optimise the dosage or reduce the likelihood of adverse effects has not been established. Safety data from several large studies indicate that the incidence of adverse effects of the drug is low and that unwanted effects are reversible.

Pharmacokinetics and Interactions of Antiepileptic Drugs

The pharmacokinetics and drug interactions of the agents of choice for treating epilepsy are examined. For effective treatment of epilepsy, target serum antiepileptic drug (AED) concentrations must be reached quickly and maintained. AEDs for acute treatment are formulated for quick absorption, while maintenance therapy is usually administered orally. AEDs have narrow therapeutic ranges. Individual differences in response necessitate that optimization of each regimen be based on the individual patient's clinical condition. Agents of choice for acute treatment are diazepam, lorazepam, midazolam, valproic acid, and phenytoin. Phenytoin, carbamazepine, valproic acid, phenobarbital, and benzodiazepines are typically used in maintenance therapy. The absorption, distribution, and metabolism or excretion characteristics of AEDs must be taken into account in optimizing the therapeutic regimen. Different AED formulations can have different absorption profiles. Drug interactions can affect all aspects of the pharmacokinetics of AEDs and should be considered when agents are removed from a regimen, as well as when they are added. Various factors can threaten seizure control and cause unexpected toxicity. Such problems can be avoided or controlled if the pharmacist is aware of the pharmacokinetics and potential interactions of the AEDs involved.

Phenobarbital and cerebral blood flow during hypotension in newborn pigs.

Phenobarbital sodium (PhS) has been used in anticonvulsant concentrations in premature newborns in attempts to prevent peri- and intraventricular hemorrhages (PIVH). Its effectiveness in preventing PIVH in clinical situations is still uncertain; however, PhS has reduced PIVH after hypertension in newborn beagles, and it has lowered cerebral blood flow (CBF) during hypertension in newborn beagles and piglets. We hypothesized that PhS might reduce CBF during systemic hypotension. Twelve control and 12 PhS-treated piglets (1 to 2 d old) were used for microsphere determinations of CBF during 1) steady state; 2) 30 min after PhS (treatment group) or saline infusion (controls); and 3 and 4) during two levels of graded hypotension. Mean arterial blood pressure (MABP) was 61 +/- 13 (SD) mm Hg (controls) and 57 +/- 13 (SD) mm Hg (PhS) during steady state. Thirty min after the PhS or saline infusion, MABP and CBF remained unchanged in both groups. CBF during hypotension at MABP of 41 +/- 5 (SD) mm Hg was significantly higher in controls than was CBF at MABP of 39 +/- 6 (SD) mm Hg in the PhS-treated group (p = 0.044); CBF in the two groups during the second hypotensive phase was not significantly different. However, LOWESS regression suggested that the CBF from the controls dropped as the arterial pressure decreased to less than 37 mm Hg, whereas PhS treatment lowered CBF during hemorrhagic hypotension compared with controls at blood pressures greater than 37 mm Hg but did not lower CBF further at lower systemic blood pressures.(ABSTRACT TRUNCATED AT 250 WORDS)

Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial

The new antiepileptic drug zonisamide was evaluated in a European multicenter parallel-group double-blind trial as add-on treatment for 139 patients with refractory partial epilepsy. During treatment with zonisamide complex partial seizures decreased by 27.7% compared to placebo ( P < 0.05) and the median rate dropped from 12/month with no changes in the placebo group ( P < 0.007). During the 12-week double-blind phase a 50% reduction of all seizures was recorded in 29.9% of the patients treated with zonisamide vs. 9.4% during placebo. Complete remission was observed during treatment with zonisamide in 6.2%. The plasma concentrations of the concomitant antiepileptic drugs did not change markedly when zonisamide was added. Adverse events, mostly fatigue, somnolence, dizziness and ataxia, occurred in 59.2% of the patients compared to 27.9% during placebo. Zonisamide was withdrawn in two patients due to adverse events. Kidney stones were not observed nor any relevant clinical chemistry or hematological changes. Zonisamide is an effective antiepileptic drug for add-on treatment of refractory partial epilepsy.

Effects of antiepileptic drug treatment on the background frequency of EEGs in epileptic patients.

The effect of changing antiepileptic drug concentrations within the therapeutic range on the EEGs of epileptic subjects was studied by quantitative EEG analysis. Twenty-seven patients had administration of one or more drugs discontinued on admission to the hospital for prolonged video/EEG monitoring, and drug levels were correlated daily with the simultaneous EEG background. Phenytoin, alone or in combination with other drugs, led to significant changes in the mean EEG background frequency and increased the percentage of power in the theta and delta bands. In the plasma ranges studied, carbamazepine, phenobarbital, and valproic acid did not lead to significant change in the EEG background frequency; however, the number of subjects taking these medications was small.

Therapeutic drug monitoring improves seizure control and reduces anticonvulsant side-effects in patients with refractory epilepsy

The benefit to patients of an on-site antiepileptic drug monitoring service, in which physicians' decisions were recorded before and after the concentration became available, have been assessed retrospectively. In 109 patients with refractory epilepsy monitored on three ( n = 61) or four ( n = 48) occasions between 1986 and 1990, one or more assay result was rated as ‘unexpected’ by the consulting doctor. In 51 of these, revision of the dose was undertaken as a consequence (active group). Their clinical outcomes were compared with those of the other 54 patients in whom the initial management plan was left unchanged (passive group). Median seizure frequency decreased in both groups, but this was statistically significant only for the actively treated patients [active group: first visit 1 (0 to 26) seizures/month, last visit 0 (0 to 19) seizures/month, P < 0.01, 95% CI −2 to −0.5; passive group: first visit 2.5 (0 to 57) seizures/month, last visit 1.5 (0 to 44) seizures/month, NS, 95% CI −1 to +10]. The number of patients reporting one or more episodes of drug-related toxicity also favoured the actively managed patients (active group 25%, passive group 56%, P < 0.01). Within this selected group of patients, the anticonvulsant concentration was a better guide to clinical management than the physician's assessment.