Antiepileptic Drug Concentrations Research Articles

Variability of antiepileptic medication taking behaviour in sudden unexplained death in epilepsy: hair analysis at autopsy

Background: Variable compliance with antiepileptic drugs (AEDs) is a potentially preventable cause of sudden unexplained death in epilepsy (SUDEP). Hair AED concentrations provide a retrospective insight into AED intake variability....

Isobolographic analysis of interactions between losigamone and conventional antiepileptic drugs in the mouse maximal electroshock model

The aim of this study was the isobolographic evaluation of interactions between losigamone (LSG), valproate (VPA), carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, and tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor coordination) and the passive avoidance task (long-term memory). Brain concentrations of antiepileptic drugs (AEDs) were measured by immunofluorescence or high-performance liquid chromatography. Isobolographic analysis indicated synergistic interactions between LSG and VPA. For example, in the proportion of 1:1 the theoretically calculated 50% effective dose for additivity (ED 50add) was 138 mg/kg, while the experimentally derived ED 50 for the mixture (ED 50mix) was 85.2 mg/kg. The difference was significant at p < 0.001. LSG combined with CBZ or PHT showed additivity, whereas the combinations of LSG with PB were either additive, for the fixed ratios of 1:3 and 1:1, or antagonistic for the ratio of 3:1 (ED 50add = 18.4 mg/kg versus ED 50mix = 26.7 mg/kg, p < 0.05). Impairment of long-term memory was noted only in the case of VPA given at its ED 50, however this AED did not affect motor performance. LSG, CBZ, PHT and PB (applied at their ED 50 values) and co-administration of LSG with conventional AEDs (including VPA) impaired neither motor performance nor long-term memory. LSG did not affect the brain concentration of VPA or PB, but significantly elevated the brain concentrations of CBZ and PHT. In contrast, VPA, CBZ and PHT significantly increased the brain concentration of LSG, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. Although LSG exhibited some favorable pharmacodynamic interactions with various AEDs, these were complicated by pharmacokinetic interactions and emphasize the importance of measuring AED concentrations in studies designed to identify desirable AED combinations.

Basic Science

Abstract Jarogniew J. Luszczki, Marta M. Andres, Piotr Czuczwar, Anna Cioczek-Czuczwar, Neville Ratnaraj, Philip N. Patsalos, and Stanislaw J. Czuczwar Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with current front-line antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV), recently introduced as an effective AED for refractory partial seizures. The mouse maximal electroshock (MES)-induced seizure model was investigated with regard to the anticonvulsant effects of carbamazepine (CBZ), phenytoin, phenobarbital (PB), valproate, lamotrigine, topiramate (TPM), and oxcarbazepine (OXC), administered singly and in combination with LEV. Acute adverse effects were ascertained by use of the chimney test, evaluating motor performance, and the passive avoidance task, assessing long-term memory. Brain AED concentrations were determined to ascertain any pharmacokinetic contribution to the observed antiseizure effect. LEV in combination with TPM exerted supraadditive (synergistic) interactions in the MES test. Likewise, the combinations of LEV with CBZ and OXC were supraadditive in this test. In contrast, all other LEV/AED combinations displayed additivity. Furthermore, none of the investigated combinations altered motor performance and long-term memory. LEV brain concentrations were unaffected by concomitant AED administration, and LEV had no significant effect on brain concentrations of concomitant AEDs. These preclinical data would suggest that LEV in combination with TPM is associated with beneficial anticonvulsant pharmacodynamic interactions. Similar, but less profound effects were seen with OXC and CBZ.

Pharmacodynamic and Pharmacokinetic Characterization of Interactions between Levetiracetam and Numerous Antiepileptic Drugs in the Mouse Maximal Electroshock Seizure Model: An Isobolographic Analysis

Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV) METHODS: With isobolographic analysis, the mouse maximal electroshock (MES)-induced seizure model was investigated with regard to the anticonvulsant effects of carbamazepine (CBZ), phenytoin, phenobarbital (PB), valproate, lamotrigine, topiramate (TPM), and oxcarbazepine (OXC), administered singly and in combination with LEV. Acute adverse effects were ascertained by use of the chimney test evaluating motor performance and the step-through passive-avoidance task assessing long-term memory. Brain AED concentrations were determined to ascertain any pharmacokinetic contribution to the observed antiseizure effect. LEV in combination with TPM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, was supraadditive (synergistic) in the MES test. Likewise, the combination of LEV with CBZ (at the fixed ratio of 16:1) and LEV with OXC (8:1 and 16:1) were supraadditive. In contrast, all other LEV/AED combinations displayed additivity. Furthermore, none of the investigated LEV/AED combinations altered motor performance and long-term memory. LEV brain concentrations were unaffected by concomitant AED administration, and LEV had no significant effect on brain concentrations of concomitant AEDs. These preclinical data would suggest that LEV in combination with TPM is associated with beneficial anticonvulsant pharmacodynamic interactions. Similar, but less profound effects were seen with OXC and CBZ.

Therapeutic Monitoring of Antiepileptic Drugs during Pregnancy and in the Postpartum Period

As in all patient populations, epilepsy is common in pregnant women. Consequently, approximately 1 in 200 pregnancies is exposed to antiepileptic drugs (AEDs). Although exposure to AEDs in utero has been associated with an increased risk of major fetal malformations, most women with epilepsy require medication throughout pregnancy, since seizures themselves may be potentially harmful not only for the mother but also for the developing fetus. Physiological changes during pregnancy result in a reduction in the serum concentrations of most AEDs, particularly in late pregnancy. Changes in protein binding lead to a greater reduction in total than free (active) drug concentrations. Pharmacokinetic changes in pregnancy show interindividual variability and are not well understood for most newer AEDs. However, recent studies have shown that changes in lamotrigine clearance are particularly marked, with increases in each trimester and a significant fall in plasma concentrations, leading to consequent breakthrough seizures in some women. Concentrations may then rise precipitously after delivery, leading to symptoms of lamotrigine toxicity. Therapeutic drug monitoring could theoretically guide adjustment of AED dosage to achieve good seizure control while minimising fetal exposure, although there are several limitations to such monitoring. Firstly, there are wide interindividual variations in serum drug concentrations, with seizure control often correlating poorly with a given therapeutic range. Secondly, therapeutic ranges have not been well defined for newer AEDs and their measurement is often not always available. Thirdly, for highly protein-bound drugs, although measurement of free drug concentrations may more accurately reflect drug availability during pregnancy than total drug concentrations, assays for this are not always available and may be unreliable. Thus, it may be useful, prior to pregnancy, to establish the total and free drug concentrations required to achieve optimal seizure control in a given individual. Regular monitoring of AEDs has been advocated in each trimester and shortly after delivery, with adjustment of dosage to avoid seizure precipitation during pregnancy or symptoms of toxicity after birth. More frequent monitoring has been recommended for lamotrigine. However, aggressive drug monitoring of any AED has yet to be proven to be effective in improving seizure control or care. Furthermore, higher doses may be associated with a greater potential for teratogenicity and it is not yet known whether longer term adverse effects may be related to in utero exposure in the latter half of pregnancy. There is limited evidence about the relationship of maternal serum drug concentrations and teratogenicity. While there is a theoretical role for therapeutic drug monitoring in improving the risk-to-benefit ratio of AED therapy during pregnancy, there are many practical limitations. Future work is needed to clarify its role in improving seizure control during pregnancy and identifying serum drug concentrations that may be considered safe for fetal exposure.

Posttraumatic seizures - prevention or not

Early posttraumatic epilepsies (EPTE) are epileptic attacks that appear in first seven days after brain injury, with incidence of 3-5%. Predictors for development of EPTE are: impressive skull fracture with rupture of dura, intracranial haemorrhage, neurogical deficit (brain contusion), and posttraumatic amnesia longer than 24 hours. It is more common in children than in adolescents and adults. It carries four times increased risk for development of late posttraumatic epilepsy. Aspects of pharmacological prophylaxis was often considered, but scientifically neglected, without clear standings regarding controversial data in literature. Patients with severe head injury, hospitalised at Neurosurgical Hospital and Pediatric Hospital, Clinical Centre University of Sarajevo, in period from 6th of April 1992 till 1st of July 1994, were included in study. Prophylaxis of EPTE was carried out with phenobarbital (2-3 mg/kg) or phenytoin (3 mg/kg) parenterally. Decision was made upon clinical findings. CT scan was done in 13.5% patients, and in 31.9% patients serum concentrations of antiepileptic drugs were monitored. 310 patients aged 0-18 years (105 patients 0-10 years, and 205 patients 11-18 years) were investigated. Predictors of EPTE presented were posttraumatic amnesia longer than 24 hours in 90.6%, neurogical deficit in 86.45%, impressive skull fracture with rupture of dura in 81.3% and intracranial haemorrhage in 40.6%. Only two boys developed EPTE in first 24 hours after injury. This study has showed that use of antiepileptic drugs can decrease incidence of EPTE. However, problem remains, management of injured patients is still highly individualised, based on different experiences of doctors that treat patient, and without clear guidelines.

Optimizing Antiepileptic Drug Therapy in the Elderly

To review and evaluate the medical literature concerning antiepileptic drug (AED) therapy in elderly patients. A MEDLINE search (1982-December 2004) was conducted. Bibliographies of the articles identified were also reviewed, and an Internet search engine was used to identify additional pertinent references. Clinical studies and reviews were evaluated, and relevant information was included. The elderly have the highest incidence of seizures among all age groups. Complex partial seizures are the most common, followed by primary generalized tonic-clonic seizures. An accurate diagnosis may prove difficult because of a low suspicion of epilepsy in the elderly and other diseases that may mimic seizures. Most AEDs are approved for treatment of elderly patients who have partial and tonic-clonic seizures. However, a number of age-related variables should be addressed when selecting an appropriate AED. Age-dependent differences in pharmacokinetics and pharmacodynamics of AEDs must be taken into account. Drug-drug interactions must be considered since elderly people often take multiple medications. The ultimate factor that often determines AED selection is tolerability. Numerous factors must be considered in treating elderly patients for seizures, but maximizing the ability of patients to tolerate drug therapy is often the basis for AED selection. Special consideration should be made along several lines, including elderly patients' cognitive functioning and their tendency to respond to lower AED concentrations.

Best Practice Guidelines for the Management of Women with Epilepsy

Being a woman with epilepsy is not the same as being a man with epilepsy. Epilepsy affects sexual development, menstrual cycle, aspects of contraception, fertility, and reproduction. MENSTRUAL CYCLE, EPILEPSY, AND FERTILITY: The diagnosis of epilepsy and the use of antiepileptic drugs (AEDs) present women of childbearing age with many problems; both the disease and its treatment can alter the menstrual cycle and fertility. CONTRACEPTION IN EPILEPSY: There are no contraindications to the use of nonhormonal methods of contraception in women with epilepsy (see Table 3). Nonenzyme-inducing AEDs (valproate sodium, benzodiazepines, ethosuximide, and levetiracetam) do not show any interactions with the combined oral contraceptive pill. There are interactions between the COCP and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [doses above 200 mg/day], and oxcarbazepine) and also lamotrigine. SEXUALITY: The majority of women with epilepsy appear to have normal sex lives, although in some women with epilepsy, both the desire and arousal phases may be inhibited. PRECONCEPTION COUNSELING: Preconception counseling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be aware of a number of issues relating to future pregnancy, including methods and consequences of prenatal screening, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labor, breast feeding, and childcare. PREGNANCY: The lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate sodium and lamotrigine is particularly teratogenic. Most pregnancies are uneventful in women with epilepsy, and most babies are delivered healthy with no increased risk of obstetric complications in women. BREAST FEEDING: All women with epilepsy should be encouraged to breastfeed their babies. The AED concentration profiled in breast milk follows the plasma concentration curve. The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant. THE CARE OF CHILDREN OF MOTHERS WITH EPILEPSY: Although there is much anxiety about the possible risks to a child from the mother's epilepsy, there is little published evidence. The risk of the child being harmed depends on the type of seizure and its severity and frequency, and this risk is probably small if time is taken to train mothers and caregivers in safety precautions. MENOPAUSE: During menopause, about 40% of women report worsening of their seizure disorder, 27% improve, and a third had no change. Hormone replacement therapy is significantly associated with an increase in seizure frequency during menopause, and this is more likely in women with a history of catamenial epilepsy. BONE HEALTH: Women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia.

Stability of Salivary Concentrations of the Newer Antiepileptic Drugs in the Postal System

Saliva antiepileptic drug (AED) concentrations strongly correlate with serum concentrations. Saliva collection is painless and noninvasive, and untrained personnel can easily be taught the collection process. Remote patients could mail saliva samples to a laboratory for monitoring, and samples could be obtained in the immediate postictal state to provide a "real-time" concentration. The objectives of this study were to assess the stability of saliva lamotrigine (LMT), levetiracetam (LEV), oxcarbazepine (OXC), topiramate (TPM), and zonsiamide (ZNS) concentrations sent through the United States Postal Service (USPS) and to quantify the amount of time needed for patients and the USPS to return samples to clinic. Saliva samples were obtained from patients currently taking 1 of the targeted AEDs. Samples were split into 2 storage vials. One sample was sealed in an addressed envelope, which the patient mailed from home, whereas the other sample was frozen immediately. Postmark date and day returned were collected for mailed samples. Saliva concentrations were determined using HPLC. Wilcoxon rank sum tests were used to compare the immediately-frozen and mailed sample means. Correlations were determined by the Spearman test. Thirty-seven patients were enrolled in the study. The median time between collection and postmark was 1 day (range 0-6 days); and between collection and receipt was 4 days (range 1-160 days). The mean concentrations for mailed and immediately frozen samples were similar for each AED (P > 0.15). Spearman rank order correlations between mailed and immediately frozen aliquots were strong (LMT rs = 1, LEV rs = 1, OXC rs = 0.964, TPM rs = 0.90, and ZNS rs = 1). Saliva samples mailed by patients maintain stability and can be returned in a reasonable length of time. Further studies are needed to assess patient/caretaker capability of obtaining an adequate sample.

Pharmacotherapy Overview of Seizure Management in the Adult Emergency Department

Seizures are a common cause of emergency department visits, and approximately 28% of epilepsy patients present to an emergency department annually for treatment. This article will provide an overview of the pharmacotherapeutic management of seizures and anticonvulsant therapy for patients who present to the adult emergency department, including practical information for pharmacists covering or cross-covering this practice area. The benzodiazepines are reviewed as a class, including dosing strategies, pharmacodynamic considerations, and advantages and disadvantages of lorazepam, diazepam, and midazolam. Indications for the use of phenytoin and fosphenytoin will be reviewed, as well as dosing, adverse effects, and cost-effectiveness data. In addition, dosing, administration, pharmacokinetics, and adverse effects of phenobarbital, carbamazepine, and valproate will be discussed. Clinical indications for serum anticonvulsant concentration monitoring and subsequent calculation of loading doses from serum concentrations are reviewed. Since status epilepticus is a life-threatening emergency, its therapeutic management is reviewed, including the use of continuous infusion midazolam, pentobarbital, and propofol. There are many opportunities for clinical pharmacists to collaborate with other members of the health care team to optimize efficacy and minimize adverse effects of anticonvulsant agents in the emergency department setting.

Reversible Cytotoxic Edema in the Splenium of the Corpus Callosum Related to Antiepileptic Treatment: Report of Two Cases and Literature Review

Clinically silent lesions localized in the splenium of the corpus callosum (SCC) are a rare finding in the magnetic resonance imaging (MRI) of patients receiving antiepileptic drugs (AEDs). They are usually of benign character but may induce unnecessary complementary examinations if their nature is unrecognized. So far, 22 cases have been described in the literature, for which different etiologies have been proposed. We describe two further cases and discuss the probable lesion etiology. We report two cases including a 25-year-old male patient and a 12-year-old female patient with a transient SCC lesion discovered in the context of a presurgical epilepsy evaluation. Comprehensive MRIs, including diffusion tensor imaging-based fiber tracking of the lesion, revealed a cytotoxic edema not disrupting neuronal fibers. Serum arginine vasopressin (AVP) measurements revealed an altered secretion during the acute phase in one patient. On the basis of our results, we hypothesize that the lesion consists of a cytotoxic edema, possibly induced by abrupt AED concentration changes and associated to alterations of AVP secretion.

Pharmacodynamic and/or pharmacokinetic characteristics of interactions between loreclezole and four conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice: An isobolographic analysis

Isobolographic analysis was used to characterize the interactions between loreclezole (LCZ) and clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced seizures and in producing acute neurotoxic adverse effects in the chimney test in mice so as to identify optimum combinations. Moreover, protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combination could be established. Any pharmacokinetic contribution was ascertained by measurement of brain antiepileptic drug (AED) concentrations. All AED combinations comprising LCZ and CZP, ETS, PB, and VPA (at the fixed ratios of 1:3, 1:1, and 3:1) were additive in their seizure suppression. However, these interactions were complicated by changes in brain AED concentrations consequent to pharmacokinetic interactions. Thus, LCZ significantly increased total brain ETS concentrations (VPA, CZP, and PB concentrations were unaffected), and ETS decreased, and VPA increased, total brain LCZ concentrations. Only combinations of LCZ with CZP and PB were completely free of any pharmacokinetic interaction. Furthermore, in the chimney test, isobolographic analysis showed that the combination of LCZ and CZP, at the fixed ratio of 1:1, was supra-additive (synergistic, P < 0.05), whereas LCZ and ETS at fixed ratios of 1:3 and 1:1 were subadditive (antagonistic, P < 0.05). The remaining combinations of LCZ with CZP (1:3 and 3:1), ETS (3:1), PB (all fixed ratios of 1:3, 1:1, and 3:1), and VPA (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. In conclusion, BI, which is a measure of the margin of safety and tolerability of drugs in combination and comprises anticonvulsant and neurotoxic measures, was favorable for only one combination (LCZ and ETS at a fixed ratio of 1:3) with a value of 1.39. In contrast, LCZ and CZP constitute an unfavorable combination (BI = 0.61–1.01). The combinations of LCZ with PB or VPA do not offer any advantage as assessed by the parameters (BI range: 0.75–0.91) used in this study. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.

Hippocampal dopamine and serotonin elevations as pharmacodynamic markers for the anticonvulsant efficacy of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine

We recently showed that dopamine (DA) and serotonin (5-HT) exert anticonvulsant effects against limbic seizures in rats mediated by hippocampal D 2 and 5-HT 1A receptor stimulation. For exogenously administered monoamines, anticonvulsant activity was only observed following 70–400% and 80–350% increases in baseline levels for dopamine and serotonin, respectively. The aim of the present microdialysis study was to investigate whether oxcarbazepine and its active metabolite, 10,11-dihydro-10-hydroxycarbamazepine (MHD) promote the release of hippocampal monoamines. Initially, concentration–response experiments were performed. Different concentrations of both compounds were perfused into the hippocampus via the microdialysis probe and tested for their effects on extracellular monoamine levels and anticonvulsant properties against pilocarpine-evoked seizures in rats. Anticonvulsant activity was always accompanied by significant increases in dopamine and serotonin levels. The anticonvulsant threshold concentrations for oxcarbazepine (100 μM) and 10,11-dihydro-10-hydroxycarbamazepine (250 μM) were associated with, respectively, 140 and 205% increases in hippocampal dopamine and 288 and 176% increases in serotonin concentrations. Co-perfusion of these anticonvulsant threshold concentrations for both compounds either with a selective D 2 or 5-HT 1A antagonist abolished all anticonvulsant effects. This study shows that oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine exert important monoamine promoting effects that, at least partly, contribute to the anticonvulsant mechanism of action of these compounds. The effects on dopamine and serotonin levels are therefore proposed as pharmacodynamic markers for the anticonvulsant activity of these compounds. These pharmacodynamic markers are here shown to be useful for the selection of anticonvulsant threshold concentrations of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine.

Carbamazepine extended-release capsules vs. oxcarbazepine: computer simulations of the effect of missed doses on drug plasma concentrations

ABSTRACTObjective: Plasma concentrations of antiepileptic drugs (AEDs) can vary and are not always an indication of clinical utility. However, adverse event occurrence can be correlated to fluctuations in plasma drug levels that occur with varying dosing regimens of the many AEDs. In this study, we present the results of computer simulations of plasma concentrations of the AEDs carbamazepine (CBZ) extended-release capsules (CBZ‐ERC) (Carbatrol) and oxcarbazepine (OXC).* Carbatrol is a registered trade name of Shire, Wayne, Pa, USAResearch design and methods: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400 mg fasting dose of CBZ‐ERC. This model was used to simulate plasma concentrations of CBZ following multiple 400 mg doses of CBZ‐ERC at 12-hour intervals, and then when a missed dose is taken 3, 6, or 9 hours late; when two doses are taken at one time; and when a single dose is taken at the time of the next dosing. In comparison, similar modeling was done for monohydroxy derivative (MHD) of OXC at doses of 600 or 1200 mg.Results: Plasma drug concentrations after 24 hours without medication were 4.1 mg/L for CBZ‐ERC, 8 mg/L for 600 mg OXC, and 16 mg/L for 1200 mg OXC. If a patient was to take only a single dose 24 hours late, it would take 24 hours to reach steady-state trough values for CBZ‐ERC, 36 hours for 600 mg OXC, and 2 days for 1200 mg OXC. The trough plasma concentration following a missed dose and the peak plasma concentration following a double dose (administered 12 hours after the missing of a dose) differed by a factor of two in the CBZ‐ERC simulation, compared with a factor of three in both OXC simulations.Conclusions: The ultimate goal of antiepileptic therapy is a seizure-free state without side effects. The current computer simulation study indicates that AEDs such as CBZ‐ERC and OXC, which produce relatively stable plasma concentrations, should be useful in attaining this goal. Nonetheless, simulated plasma concentrations resulting from CBZ‐ERC treatment tended to oscillate less dramatically compared with simulated plasma concentrations resulting from treatment with 600 or 1200 mg OXC.

The role of common variation in drug transporter genes in refractory epilepsy

Resistance to antiepileptic drugs (AEDs) is one of the most serious clinical problems in epilepsy, and along with AED teratogenicity, perhaps the major concern of epilepsy pharmacogenetics. Studying the genetics of drug resistance in epilepsy is important, as it may identify or confirm key mechanisms underlying this phenomenon that have real clinical importance; it might also offer insights into its prediction and management. Drug resistance in epilepsy is likely to be multifactorial: overactivity of multi-drug transporters provides one likely underlying mechanism through lowering of AED concentration in the epileptogenic focus. Genetic association studies may provide a tool to assess this ‘transporter’ hypothesis by determining whether differences between individuals contribute to resistance phenotypes. Most of these studies have investigated one variant in the ABCB1 gene, and have provided, thus far, inconclusive evidence. This review also considers current knowledge of the role of genetic polymorphisms in multi-drug transporters in pharmacoresistant epilepsy, to highlight possible confounding factors affecting the implementation and interpretation of association studies in this field.

In Vivo Modulatory Action of Extracellular Glutamate on the Anticonvulsant Effects of Hippocampal Dopamine and Serotonin

Our recent work (Clinckers et al., J Neurochem 2004;89:834-43) demonstrated that intrahippocampal perfusion of 2 nM dopamine or serotonin via a microdialysis probe offered complete protection against focal pilocarpine-induced limbic seizures and did not influence basal extracellular hippocampal glutamate levels. Ten nanomolar dopamine or serotonin perfusion, however, worsened seizures and was accompanied by significant extracellular glutamate increases to approximately 200%. The significance of these glutamate elevations in seizure generation remains unclear. The present microdialysis study investigated the modulatory role of extracellular hippocampal glutamate levels in these monoaminergic protective and proconvulsant effects. A first group of male Wistar albino rats was perfused intrahippocampally for 240 min with 6.25 microM glutamate alone to increase extracellular levels by 200%. Other animals were perfused with anticonvulsant concentrations of monoamines throughout the experiments while receiving continuous coperfusions of 6.25 microM glutamate either before, during, and after (240 min) or only after (100 min) pilocarpine perfusion (40 min). Rats were scored for epileptic behavior, and the mean scores were compared with those of the control group. Microdialysates were analyzed for monoamine and glutamate content with microbore liquid chromatography. No convulsions occurred during glutamate perfusion alone. When monoamines and glutamate were coperfused before pilocarpine administration, the anticonvulsant effect of the monoamines was lost. Glutamate addition after pilocarpine administration did not affect monoaminergic seizure protection. These results indicate that extracellular glutamate increases per se do not necessarily induce seizures but that they can modulate the anticonvulsant effects exerted by hippocampal monoamines.

Free Communications: Psychosocial Aspect

Abstract Effects of Ethyl Loflazepate for Children with Refractory Epilepsy Accompanied by Severe Motor and Intellectual Disabilities. 1 Hideaki Kanemura, 1 Masao Aihara, and 1 Shinpei Nakazawa ( 1 Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan ). Purpose: Ethyl lofrazepate has been used mainly as an antianxiety agent. Recently, ethyl lofrazepate has been reported to demonstrate good efficacy for acute epilepsy, seizure clusters, and serial seizures. Hypersecretion and hypersalivation are problematic adverse reactions in infants and children treated with benzodiazepine drugs. However, ethyl lofrazepate may have a lower incidence of hypersecretion and hypersalivation compared to other benzodiazepine drugs. We report the efficacy of ethyl lofrazepate in three children with refractory epilepsies accompanied by severe motor and intellectual disabilities. Methods: The subjects comprised three symptomatic localization-related epileptic patients aged 2–8 years with severe motor and intellectual disabilities. All patients had some difficulties in seizure control with standard antiepileptic drugs (AEDs). They had multiple seizure types, including simple partial seizures, complex partial seizures, tonic, myoclonic, and generalized tonic–clonic seizures. Prior to starting ethyl lofrazepate, they had difficulty in breathing due to hypersecretion and hypersalivation induced by benzodiazepine drugs. Parents and caregivers, including nursing staff, were requested to keep seizure diaries for seizure counts. The basic strategy was add-on therapy, in which ethyl lofrazepate was additionally given with standard doses of the AEDs. During the titration phase, concomitant benzodiazepine, if any, was gradually withdrawn and discontinued. Ethyl lofrazepate was started at a dose of 0.015 mg/kg and was increased to 0.05 mg/kg in the second week. Ethyl lofrazepate was taken twice a day in the morning and at night. Clinical laboratory tests including antiepileptic drug levels, blood chemistry, and hematology were performed at baseline, and 2, 4, 8, and 12 weeks after reaching the maximum dose of ethyl lofrazepate. EEGs were obtained from all patients at the same time points. Informed consent was obtained from the parents. Results: Seizures were reduced during the first 12 weeks of treatment with ethyl lofrazepate in all three patients (100%). Two patients became seizure free, and one patient demonstrated at least a 90% reduction. All seizure types were reduced by ethyl lofrazepate. The sample size was too small to determine if any particular seizure type was more affected than any other. The response to ethyl lofrazepate was observed within 6 weeks of initiating treatment. One patient had complete cessation of seizures at 2 weeks and another patient became seizure free at 4 weeks after reaching the maximum dose of ethyl lofrazepate. Epileptic discharges were suppressed in two cases and demonstrated at least 75% reduction in one case. No alteration in blood chemistry or hepatic function was observed in any patient. Blood concentrations of other AEDs were unaffected before and after therapy. No adverse reactions such as hypersecretion or hypersalivation were observed. Respiratory status improved markedly in all patients. There were no other adverse effects that required dose reduction of ethyl lofrazepate in all cases. None had a recurrence of seizures or adverse effects such as hypersecretion or hypersalivation at 6-, 8- and 9-month follow-up of ethyl lofrazepate therapy. Conclusion: The results of our prospective study indicate that ethyl lofrazepate is an effective and safe benzodiazepine for the treatment of refractory epilepsy with severe motor and intellectual disabilities. Dramatic improvement (over 90% reduction in seizure frequency, including complete cessation) was observed in all cases. Unlike other benzodiazepines, adverse effects, such as hypersecretion and hypersalivation, were less noticeable. Based on this study, we conclude that ethyl lofrazepate is an effective adjunctive antiepileptic drug for refractory epileptic children with severe motor and intellectual disabilities complicated by respiratory failure. Further studies are necessary to determine whether these effects are transient or permanent.

Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: A pooled analysis of data from randomized clinical trials

The purpose of this study was to determine the influence of levetiracetam on the steady-state serum concentrations of other commonly used antiepileptic drugs (AEDs). Serum AED concentrations were measured at baseline and after adjunctive therapy with levetiracetam (1000–4000 mg/day) or placebo in four phase III trials in patients with refractory partial epilepsy receiving stable AED dosages. The data were pooled, and repeated measures covariance analysis was used to calculate the ratio (and 90% confidence intervals) of the geometric mean serum drug concentrations during adjunctive levetiracetam therapy relative to baseline. Levetiracetam did not increase or decrease mean steady-state serum concentrations of carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. For each of these AEDs, the 90% confidence interval of the geometric mean drug concentrations ratio was included within the 80–125% bioequivalence range. Serum concentrations of these AEDs did not change over time after adjunctive levetiracetam therapy, irrespective of the dosage of levetiracetam used. For vigabatrin, there was no evidence for a significant change in serum drug concentration after the addition of levetiracetam, but the number of observations was too small for the limits of the confidence interval to fall within the 80–125% range. Thus, adjunctive therapy with levetiracetam does not influence the steady-state serum concentrations of concomitantly administered carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. Consequently, no need for adjusting the dosages of these AEDs is anticipated when levetiracetam is added on or removed from a patient's therapeutic regimen.

Beneficial interaction between vigabatrin and valproate against seizures induced by pentylenetetrazole in mice

The anticonvulsant effects of adding a non-protective dose of vigabatrin (VGB) to increasing single doses of sodium valproate (VPA) against seizures induced by 110 mg kg −1 of pentylenetetrazole (PTZ) or by 4.5 mg kg −1 of picrotoxin (PIC) were compared in CD1 mice with those of VPA alone and vice versa. Neurotoxicity was evaluated by the rotarod test. The study also assessed changes in concentrations of anticonvulsants, γ-aminobutyric acid (GABA) and glutamate in the whole brain. VGB increased the potency ratio of VPA against PTZ (1.62, P < 0.05) but not against PIC (1.08, n.s.). VGB slightly decreased the neurotoxicity of VPA (0.93, n.s.) and the protective index of VPA was, therefore, increased from 1.93 to 3.34 for the PTZ model and from 1.40 to 1.61 for the PIC model. VGB did not modify brain concentrations of VPA, and increased brain GABA in relation to VPA alone. On the other hand, VGB did not achieve a complete protection neither against seizures induced by PTZ nor against seizures induced by PIC and a non-protective dose of VPA did not significantly modify the effects of increasing doses of VGB. In conclusion, the addition of a non-protective dose of VGB increased the anticonvulsants effects and the protective index of VPA in the PTZ model. A more than expected brain GABA increase together with the lack of a pharmacokinetic interaction support a pharmacodynamic basis for this interaction.

Anticonvulsant action of GBR-12909 and citalopram against acute experimentally induced limbic seizures

We recently showed that intrahippocampally administered dopamine and serotonin exert concentration-dependent non-protective, protective and proconvulsant effects against limbic seizures in rats. Anticonvulsant action was mediated via, respectively, hippocampal D 2 and 5-HT 1A receptor stimulation, while proconvulsant effects were associated with concomitant hippocampal glutamate increases. We here examined whether increases in endogenous hippocampal dopamine and serotonin exert similar actions. Initially, dose-response experiments were performed with intrahippocampal perfusions of GBR-12909 and citalopram, respectively, selective dopamine and serotonin re-uptake blockers. Based on their effects on monoaminergic release, a potential non-protective, protective and proconvulsant concentration was selected. The predicted non-protective GBR-12909 (10 μM) and citalopram (0.5 μM) concentrations failed to prevent pilocarpine-induced seizures. The predicted protective GBR-12909 (100 μM) and citalopram (1 μM) perfusions resulted in complete anticonvulsant action, again mediated by D 2 and 5-HT 1A receptors. Unexpectedly, at predicted proconvulsant concentrations complete anticonvulsant action was obtained and hippocampal Glu remained unaltered. This study shows that selective monoamine re-uptake blockers have important anticonvulsant properties. Based on the previously established anticonvulsant monoamine ranges, anticonvulsant threshold concentrations can be predicted for compounds with endogenous dopamine or serotonin promoting effects. Non-selective actions curtailing glutamatergic activity may further be responsible for the unexpected anticonvulsant effects at predicted proconvulsant concentrations.