Antiepileptic Drug Concentrations Research Articles

Preclinical profile of combinations of some second-generation antiepileptic drugs: an isobolographic analysis.

The need for an efficacious treatment of patients with intractable seizures is urgent and pressing, because approximately 30% of epilepsy patients worldwide are still inadequately medicated with current frontline antiepileptic drugs (AEDs). This study sought to determine the interactions among some newer AEDs [topiramate (TPM), felbamate (FBM), oxcarbazepine (OXC), and lamotrigine (LTG)] in the maximal electroshock-induced seizures (MES) and chimney test (motor performance) in mice, by using the isobolographic analysis. Evaluation of the anticonvulsant and acute adverse (neurotoxic) effects in mice produced by the AEDs in combinations at the fixed ratios of 1:3, 1:1, and 3:1 allowed the assessment of their preclinical profile and the determination of benefit indices (BIs) for all individual combinations. Combinations of TPM+FBM at the fixed ratios of 1:3, 1:1, and 3:1 offered supraadditive (synergistic) interactions against electroconvulsions and subadditivity (antagonism) in terms of acute neurotoxic effects in the chimney test (BIs ranged between 1.90 and 2.59, the best combinations from a preclinical point of view). The examined combinations of TPM+OXC also were advantageous due to synergistic interactions in the MES, and additivity in terms of acute neurotoxic effects produced by the AEDs (BIs ranged between 1.35 and 1.71). In contrast, OXC+FBM exerted subadditive (antagonistic) interactions in the MES test and additive interactions in terms of acute motor impairment of animals (BIs ranged between 0.53 and 0.71). The worst combination was observed for OXC+LTG, at the fixed ratio of 1:1, displaying subadditivity (antagonism) against electroconvulsions and supraadditivity (synergy) with respect to neurotoxicity (BIs, 0.43). The remaining combinations of OXC+LTG tested (i.e., 1:3 and 3:1) exerted additivity in the MES test and supraadditivity in the chimney test (BIs 0.54 and 0.49, respectively). None of the studied AEDs affected the brain concentrations of other AEDs, so the existence of any pharmacokinetic interactions to be responsible for the observed effects is improbable. Based on the current preclinical data, the pharmacological profile of combinations of TPM+FBM and TPM+OXC evaluated with isobolography was beneficial and might be worth recommendation to further clinical practice. In contrast, utmost caution is required during the use of OXC+FBM or OXC+LTG in clinical practice, because of the high risk of neurotoxic adverse effect appearance.

Selective and persistent upregulation of mdr1b mRNA and P-glycoprotein in the parahippocampal cortex of chronic epileptic rats

There is recent evidence that increased expression of multidrug transporters, such as P-glycoprotein (P-gp), may lead to reduced antiepileptic drug (AED) concentrations in the brain, shortly after status epilepticus (SE), thereby suggesting a possible mechanism for drug-resistance. To get insights on whether increased P-gp expression is a consequence of the initial insult, or evolves more gradually as a result of recurrent spontaneous seizures, we used a rat model of temporal lobe epilepsy in which spontaneous seizures develop after an electrically induced SE. We investigated the temporal and region-specific expression of two isoforms of the multidrug resistance gene (mdr1a and mdr1b, both encoding for P-gp) in two regions within the temporal lobe (the dentate gyrus (DG) and the parahippocampal cortex (PHC)). Using real-time PCR, we found that the mdr1b isoform was increased in the temporal lobe, 1 week after SE; however, this increase was reversible in dentate gyrus while it persisted in the parahippocampal cortex of chronic epileptic rats. Mdr1b upregulation was related to the occurrence of spontaneous seizures, since this isoform was unchanged in rats that were stimulated, but that did not develop SE (non-SE). The mdr1a isoform was transiently upregulated in the dentate gyrus. P-gp immunostaining was enhanced in endothelial and glia-like cells, 1 week after SE. In chronic epileptic rats, the number of strongly P-gp positive glia-like cells was much lower than 1 week after SE, and it was mainly present in the most ventral part of the temporal lobe. These cells were in close appostion to strongly stained blood vessels. These findings show that both mdr1a and mdr1b are induced by SE, although the increase in mdr1b isoform was more persistent. More importantly, increased P-gp expression is still present in chronic epileptic rats.

Influence of coadministered antiepileptic drugs on serum antiepileptic drug concentrations in epileptic patients -quantitative analysis based on suitable transforming factor

We conducted a study to clarify the most suitable transforming factor related to the daily dose of antiepileptic drugs (D) providing a steady-state serum concentration (C(t)) and analyzed the influences of the concomitant use of antiepileptic drugs on C(t) quantitatively. Data obtained by routine therapeutic drug monitoring from epileptic patients treated with the multiple oral administration of valproic acid (VPA), carbamazepine (CBZ), zonisamide (ZNS), phenobarbital (PB), and phenytoin (PHT) were used for the analysis. Employing the ideal body weight or the extracellular water volume as a transforming factor, allowed the level/dose (L/D) ratio to be independent of the patient's age and gender for monotherapy with VPA or CBZ, ZNS, PB, and PHT, respectively. Each C(t) was revealed to be dependent on only one variable in terms of the transformed daily dose (D'). C(t) was proportional to the power function of D' for VPA and CBZ and was linearly proportional to D' for ZNS and PB. The L/D ratio is expressed as a linear function of C(t) for PHT. For a detailed analysis of the influences of the coadministered antiepileptic drugs, we defined the parameter as an alteration ratio, representing the influence of each antiepileptic drug on the C(t) of VPA and CBZ alone, and on the L/D ratio of ZNS and PB alone, respectively. A model based on the assumption that each value of an alteration ratio was independent from one other and multiplicative for VPA, CBZ, and ZNS, and that the coadministered drug inhibited the drug-metabolizing enzyme competitively for PB, was adopted. The Michaelis-Menten kinetic model was adopted for PHT. The analysis clarified that CBZ, PB, and PHT significantly lowered (P<0.05) C(t) to 0.81, 0.88, and 0.83 compared with the value of VPA alone, that PB and PHT significantly lowered C(t) to 0.77 and 0.71 compared with the value of CBZ alone, and that VPA, CBZ, PB, and PHT significantly lowered the L/D ratio of ZNS alone to 0.87, 0.85, 0.85, and 0.80, respectively. VPA, CBZ, and PHT significantly increased (P<0.05) the L/D ratio of PB to 1.47, 1.18, and 1.19, respectively. The daily PHT dose was decreased to 0.89, 0.91, 0.90, and 0.84 the dose of PHT alone to maintain C(t) in the therapeutic range when VPA, CBZ, ZNS, and PB were coadministered, respectively. In the case of the addition or discontinuance of concomitant treatment with antiepileptic drugs in the same patient, the estimated C(t) values were calculated using the value of each alteration ratio and compared with the measured ones. Each mean of prediction error was about 20%. Our results appear valid and these alteration ratios should be available for clinical use.

Principles of antiepileptic drug treatment of epilepsy.

For the successful treatment of epilepsy, accurate diagnosis of epilepsy and epileptic seizures, and proper selection of antiepileptic drugs (AED) according to the classification of epileptic syndromes are fundamentally important. Efficacy of AED treatment, however, depends not only on its pharmacological action but also on its efficient use, namely a rationally thinking tailor-made treatment considering the characteristics of each patients, i.e. individual differences in pharmacokinetics, factors influencing AED concentrations, AED interactions, and comprehensively their life style and psychosocial factors.

Hormones and seizures.

The opposing effects of estrogen (proconvulsant) and progesterone (anticonvulsant) on seizure threshold have been noted in animal and human studies. Levels of these hormones fluctuate throughout the menstrual cycle, and, in some women with epilepsy, these fluctuations may be related to the occurrence of seizures around the time of menses or an increase in seizures in relation to the menstrual cycle, also known as catamenial epilepsy. Variations in concentrations of antiepileptic drugs across the menstrual cycle may also contribute to increased seizure susceptibility. Diagnosis of catamenial epilepsy requires careful assessment of menstrual and seizure diaries and characterization of cycle duration and type. While there are several approaches to the treatment of catamenial epilepsy, each is based on small, unblinded studies or anecdotal reports. It is important for the physician to work closely with the patient to determine whether her seizures are indeed catamenial and to design an appropriate treatment plan.

Physician preference for antiepileptic drug concentration testing

A four-item questionnaire asked active U.S. members of the Child Neurology Society to value painless antiepileptic drug concentration monitoring, whether members had ordered a saliva level (the best established painless method) in the last year, and whether such levels were available. Value was quantified by time per patient that the physician would willingly expend to arrange for the test. Of 945 questionnaires sent, 544 (58%) were returned. When asked the value of a painless method for children, 286/522 (55%) reported willingness to expend 10 to 30 minutes to arrange the test; 498/522 (95%) would use a painless method if available. When asked the value of an immediate sample at home during a seizure or adverse event, a substantial majority, 370/526 (70%), would make an important donation of their own time to arrange for the sample. Only 5% would not use it. Just 2/544 respondents had obtained a painless (saliva) concentration, and merely 33/544 (6%) perceived such tests as being available. We conclude that child neurologists put a high value on painless antiepileptic monitoring. These data suggest that a painless method of measuring antiepileptic drug concentrations—especially if it could be performed at home—would fulfill an unmet need in the care of children with epilepsy.

Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR- rats.

Different adenosine triphosphate (ATP)-driven multidrug transporters have been described to be expressed in the luminal membrane of blood-brain barrier (BBB) endothelial cells. At this site, multidrug transporters have been suggested to restrict penetration of drugs into the brain. Increasing evidence suggests that overexpression of different multidrug transporters occurs in the region of the epileptic focus of pharmacoresistant epilepsy patients. Based on the assumption that antiepileptic drugs (AEDs) are substrates of these transporters, this overexpression may limit access of AEDs to epileptic neurons and may contribute to drug-refractoriness. In a recent study, overexpression of multidrug resistance protein 2 (ABCC2; MRP2) was reported in BBB endothelial cells of epileptic focal tissue from pharmacoresistant patients. With brain microdialysis, we recently demonstrated that the AED phenytoin is subject to transport by ABCC2 at the BBB, whereas phenobarbital does not seem to be a substrate of ABCC2. We investigated whether ABCC2 is functionally involved in transport of the AEDs carbamazepine (CBZ), lamotrigine (LTG), and felbamate (FBM) across the BBB. The distribution of these AEDs into the brain of ABCC2-deficient TR- rats was determined. AED concentrations in plasma and brain extracellular space of these mutant rats did not differ significantly from those of rats of the corresponding background strain. In the amygdala-kindling model of epilepsy, the anticonvulsant efficacy of LTG and FBM was comparable in both groups of rats. In contrast, CBZ exhibited a higher anticonvulsant activity in kindled ABCC2-deficient rats as compared with nonmutant rats. In this present study, the microdialysis results gave no evidence that ABCC2 function modulates entry of CBZ, LTG, and FBM into the CNS of naïve rats. However, ABCC2 deficiency was associated with an increased anticonvulsant response of CBZ in the kindling model. Future investigations are planned to identify the underlying mechanism for this difference, clarifying whether a pharmacokinetic difference is detectable only when brain access of CBZ is compared in kindled ABCC2-deficient rats and kindled nonmutant rats, which may have an increased expression of ABCC2 in response to seizures. The data substantiate that ABCC2-deficient TR- rats are a useful tool for defining the role of ABCC2 for transport of AEDs, and give evidence that the use of kindled TR- rats may provide important supplementary information.

Interactions between non-barbiturate injectable anesthetics and conventional antiepileptic drugs in the maximal electroshock test in mice—an isobolographic analysis

The aim of this study was the isobolographic evaluation of interactions between three non-barbiturate intravenous anesthetics and conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Obtained results indicate that ketamine acts synergistically with valproate and carbamazepine. Also the combinations of propofol and valproate or phenobarbital led to synergistic interactions. An antagonism was found between etomidate and carbamazepine or phenobarbital. On the other hand, interactions between diphenylhydantoin and injectable anesthetics proved to be additive. The only exception was the combination of diphenylhydantoin and propofol (1:3). Pharmacokinetic phenomena do not seem to interfere with the observed interactions, since none of anesthetics influenced the free plasma concentrations of antiepileptic drugs. Referring to undesired effects, only propofol impaired long-term memory. Although propofol did not disturbed motor coordination, it enhanced motor impairment caused by carbamazepine and diphenylhydantoin. Results of the present study suggest that etomidate needs to be avoided in epileptic patients due to a possibility of negative interactions with some antiepileptic drugs and seizure precipitation.

Antiepileptic drug pharmacokinetics during pregnancy and lactation.

The ideal management of women with epilepsy during pregnancy and the postpartum period involves achieving an optimal balance between minimizing fetal and neonatal exposure to the deleterious influences both of antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiologic changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Noncompliance can also be a major factor. The majority of AEDs are characterized by significant increases in clearance during pregnancy. Lamotrigine (LTG) clearance markedly increases throughout pregnancy, to an extent greater than with the older AEDs. Studies during and after birth in mothers taking the older AEDs indicate extensive transplacental transfer and low to moderate excretion into breast milk. Limited studies of the newer AEDs indicate similar extensive transplacental transfer [LTG, oxcarbazepine, topiramate (TPM), zonisamide (ZNS)], and breast milk/maternal plasma concentration ratios less than 1 (LTG, TPM, ZNS). Especially high excretion of levetiracetam into breast milk may occur. Current published guidelines recommend that the ideal AED concentration should be established for each patient before conception and that monitoring of AED concentrations should be performed during each trimester and in the last month of pregnancy. Free concentrations should be measured for phenobarbital, phenytoin, carbamazepine, valproic acid, and primidone. Some authors recommend at least monthly monitoring of AED concentrations, especially for LTG. Future studies of formal pharmacokinetic modeling of AEDs during pregnancy and the postpartum period could provide an important step toward achieving effective drug dosing to maintain therapeutic objectives for the mother but, at the same time, to minimize fetal drug exposure.

Appropriateness of Anticonvulsant Concentration Monitoring In Hospitalized Pediatric Patients

We assessed the appropriateness of anticonvulsant concentration monitoring in hospitalized pediatric patients admitted to a teaching hospital. Literature-based criteria for anticonvulsant concentration monitoring were approved by the Pharmacokinetic and Neurology Services of Le Bonheur Children's Medical Center. A random sample of anticonvulsant concentrations ordered over a 6 month period was assessed. Patient demographics, anticonvulsant data, the type of professional who recommended the concentration, and sampling time were collected concurrent with hospitalization. Concentrations were assessed for appropriateness of indication and sampling time. Concentrations (n=141) were obtained in 74 patients (mean age = 6.5+5.5 years) admitted to the floor (86%) or ICU (14%). Length of stay was 8.3+16.9 days. Monotherapy was used in 78.3% of patients. Carbamazepine (28.4%), phenytoin (27.5%), phenobarbital (27.6%), valproate (14.8%) or free phenytoin (1.7%) concentrations were recommended by a pediatrician (70.5%), neurologist (21.5%), neurosurgeon (2.1%), or Pharmacokinetic Services (5.9%). Fifty-three percent of all concentrations met appropriateness criteria for indication; however, 8.5% of tests were collected incorrectly. About half of the concentrations recommended by pediatricians (47.5%), neurologists (43.3%), and neurosurgeons (66.7%) did not meet appropriateness criteria for indication. The main reasons for inappropriate anticonvulsant concentration monitoring include frequent repetitive sampling (<24 hours), obtaining an anticonvulsant concentration without an appropriate indication, failure to correctly apply the concept of pharmacological steady-state, incorrect identification of drug-drug interactions, and sampling irrespective of dosing schedule. One-half of all anticonvulsant concentrations fulfilled the indication criteria. There was no difference in appropriateness of indication based on the service recommending the concentration or for each specific anticonvulsant. The appropriateness rates reported are comparable to those reported in other studies. Inappropriate anticonvulsant concentration monitoring fails to improve patient care and contributes to a significant waste of financial resources.

Anticonvulsant use in elderly patients in long-term care units.

Elderly patients in long-term care units are frailer than their community-dwelling peers and may be more at risk from toxic side-effects of anticonvulsant medication at standard doses. To examine the prescribing of anticonvulsants to patients in elderly care units. Drug prescription sheets and case notes were reviewed. Serum anticonvulsant concentration, renal and liver profiles and albumin level were measured. Anticonvulsants were prescribed to twice as many male as female patients (32 vs 14%; p<0.03) and to 33% of those younger than 80 years of age versus 10% of those aged 80 years or older (p<0.0002). No patient had significant hypoalbuminaemia and routine measurement of serum anticonvulsant concentration did not indicate an alteration of dosage. Anticonvulsants appear to be well tolerated in these patients. The younger age of those receiving anticonvulsants is inadequately explained by the characteristics of the patient cohort and may reflect a shift towards a younger age in patients requiring anticonvulsants due to increased mortality in this group.

Interactions of tiagabine with some antiepileptics in the maximal electroshock in mice

Tiagabine (TGB), a new potent γ-aminobutyric acid (GABA) uptake inhibitor, is widely applied in adjunctive treatment of partial seizures in humans. Although, polytherapy is not an initial method of epilepsy treatment, clinicians often combine TGB with other antiepileptics as add-on therapy for assuring the anticonvulsant protection in patients with refractory seizures. To evaluate the character of pharmacological interactions between TGB and some antiepileptics, the isobolographic analysis was used as a suitable method for determining the exact types of interactions. Determination of an influence of TGB on the protective effects of diphenylhydantoin (DPH), carbamazepine (CBZ), valproate (VPA), phenobarbital (PB), lamotrigine (LTG), topiramate (TPM), and felbamate (FBM) in maximal electroshock-induced seizures was essential for this study. To exclude or confirm a pharmacokinetic character of observed interactions, the free plasma and brain concentrations of antiepileptic drugs (AEDs) studied were evaluated by using the immunofluorescence or high-pressure liquid chromatography (HPLC). TGB (up to 2.5 mg/kg) remained ineffective upon the electroconvulsive threshold, whilst the drug in doses of 5 and 10 mg/kg significantly raised the electroconvulsive threshold in mice. According to the isobolography, TGB appears to act synergistically with VPA. The remaining combinations tested exerted additive interactions. A pharmacokinetic character of interaction between TGB and VPA was evidently corroborated either in plasma or brains. Moreover, TGB significantly reduced the plasma and brain concentrations of DPH; however, pharmacokinetic events were not accompanied by any changes in anticonvulsant activity of the latter. Finally, the isobolographic analysis revealed that combinations of TGB with VPA exerted synergistic (supra-additive) interaction resulting from a pharmacokinetic interaction.

Is the interaction between felbamate and valproate against seizures induced by 4-aminopyridine and pentylenetetrazole in mice beneficial?

We compared the effects of adding a non-protective dose of valproate (VPA) to increasing single doses of felbamate (FBM) with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by 14 mg kg −1 of 4-aminopyridine (4-AP) and by 110 mg kg −1 of pentylenetetrazole (PTZ), and neurotoxicity by the rotarod test. The study also assessed changes in concentrations of anticonvulsants, γ-aminobutyric acid (GABA) and glutamate in the whole brain. VPA increased the potency ratio of FBM against 4-AP (1.94, P<0.05) but not against PTZ. VPA increased the neurotoxicity of FBM (3.30, P<0.05) and the protective index of FBM was, therefore, reduced from 12.0 to 7.0 for the 4-AP model and from 11.8 to 5.2 for the PTZ model; VPA reduced brain FBM, and increased brain GABA in relation to FBM monotherapy. On the other hand, FBM increased the potency ratio of VPA against 4-AP (1.60, P<0.05) but not against the PTZ, and had no effect on the rotarod model. Therefore, the protective index increased from 1.1 to 1.6 for the 4-AP model and decreased from 1.9 to 1.7 for the PTZ model. FBM did not change brain VPA, and changes in brain GABA and glutamate were not clearly related to anticonvulsant effects. In conclusion, although the addition of a low dose of FBM to VPA was beneficial in the 4-AP model, the addition of a low dose of VPA to FBM was not; both combinations were disadvantageous in the PTZ model. This interaction appears to be pharmacodynamic because a pharmacokinetic mechanism was discarded.

Mechanisms of antiepileptic drug resistance.

The present review considers new developments in the study and our understanding of resistance to treatment with antiepileptic drugs in epilepsy. Studies suggest that mechanisms of resistance to drug treatment that operate in other diseases may also be relevant in human and animal drug-resistant epilepsy. Immunohistochemical and molecular genetic data show that there is overexpression of a number of genes and proteins that mediate nonspecific resistance to drug treatment. In particular, there is upregulation of P-glycoprotein and multidrug resistance-associated proteins 1 and 2. These proteins appear to be expressed in cerebral parenchymal cell populations that do not normally do so. Work in animal models suggests that these proteins are able to reduce the local concentration of antiepileptic drugs. Although these proteins are therefore good candidates for mediators of drug resistance, there is still limited proof that they are functionally important in human drug-resistant epilepsy. Careful attention needs to be given to the identification and confirmation of the practical importance of mechanisms postulated to underlie drug resistance in human epilepsy. If certain mechanisms are shown to be involved, then new therapeutic options for drug-resistant human epilepsy may be forthcoming.

Comment

As described in these case vignettes, any strategy for the drug treatment of epilepsy in a patient with AIDS, asthma, or stroke needs to take into account the clinical importance of the P450 cytochromes (CYP) and the potential impact that antiepileptic drugs (AEDs) may have on the disease process. The human CYP superfamily comprises 57 genes. These genes code for enzymes that can have, among a host of other functions, a role in the metabolism of AEDs and vitamin D synthesis and metabolism [ [1] Nebert D.W. Russell D.W. Clinical importance of the cytochromes P450. Lancet. 2002; 360: 1155-1162 Abstract Full Text Full Text PDF PubMed Scopus (1087) Google Scholar ]. For our cases, these two aspects are particularly relevant. Hepatic concentrations of human CYP enzymes are increased by consumption of many of the drugs that are prescribed for epilepsy. This induction leads to enhanced clearance of other drugs that are also CYP substrates. The ability of one CYP substrate to affect the concentration of another in this manner is the basis for so-called drug–drug interactions, which complicate treatment as seen in our cases. In addition, AEDs may also inhibit CYP enzymes; for example, valproate is a broad enzyme inhibitor and affects many drug clearance pathways, while phenytoin, carbamazepine, phenobarbital, and primidone are broad examples of enzyme inducers. Such inhibitory drug–drug interactions are even more disturbing as they may lead to decreased clearance with ensuing toxicity due to increasing serum concentrations of AEDs given in combination.

An open-label study of levetiracetam at individualised doses between 1000 and 3000 mg day −1 in adult patients with refractory epilepsy

Background: The novel antiepileptic drug (AED) levetiracetam (LEV, Keppra ®) is indicated as adjunctive therapy for partial epilepsy. The primary aim of this study was to measure the safety and tolerability of LEV individualised dosing in a heterogeneous refractory epilepsy population. Methods: LEV was evaluated in a 10- to 16-week open-label, multicentre study in adult patients with epilepsy refractory to previous treatment with at least two AEDs. Individualised LEV doses up to 3000 mg day −1 were determined in an initial up-titration phase, and optimal doses were administered as adjunctive treatment during an 8- to 10-week evaluation period. Concomitant AEDs and their doses could not be changed during the study. Safety and tolerability were monitored by expression of adverse events as well as by retention rate. The effect of LEV on concomitant AED concentration was also studied. Efficacy was assessed using global clinical evaluation (GCE) scores, seizure frequency, and ≥50% responder rate. Results: LEV therapy was initiated in 219 patients; 183 had localisation-related epilepsy and 37 had generalised epilepsy. In one patient, epileptic syndrome was defined as both localisation-related and generalised. About 81.7% (179/219) continued and completed treatment throughout the study, and 79% (172/219) chose to continue LEV in a follow-up study. The most common adverse events were asthenia, dizziness, and somnolence. Most adverse events occurred during up-titration. LEV treatment did not alter the concentration of concomitant AEDs. LEV improved GCE scores in 79.5% (152/191) of patients. LEV reduced the median total seizure frequency of all patients from a median of 2.25 seizures per week at baseline ( n=219) to 1.10 seizures per week during the evaluation period ( n=191 patients with at least one seizure count during evaluation). The ≥50% responder rate was 48.2% for all seizure types, 49.4% for partial-onset, and 51.4% for generalised-onset seizures. Throughout the evaluation period (i.e. from the start of the evaluation period until completion or early discontinuation), 26/191 (13.6%) had a 100% reduction in total seizure frequency, while in a follow-up study, 10.5% (18/172) were seizure-free for at least 6 months and 6.4% (11/172) were seizure-free for at least 1 year. Conclusion: LEV was well tolerated, as evidenced by limited adverse event reporting and the high retention rate, and appeared effective in both generalised and partial epilepsy.

Pharmacokinetic considerations in the treatment of childhood epilepsy.

Organogenesis throughout childhood affects almost every aspect of pediatric pharmacotherapy. The antiepileptic drugs (AEDs) are particularly impacted since most elimination rates are diminished for the first 6 months of infancy, but quickly attain and supersede adult values. When children enter a hypermetabolic stage, large doses of AEDs may be necessary to maintain effective serum concentrations. Medication noncompliance is frequently confused as hypermetabolism, since both present with low serum drug concentrations. Amazingly, noncompliance among children with chronic illness approaches a similar incidence to that reported in the adult population. It is obviously important to include this in the differential diagnosis of the etiology of subtherapeutic serum AED concentrations. Maturational differences also affect gastrointestinal drug absorption. Intestinal transit time and absorptive surface area are both diminished in young children. Drug delivery systems suitable in adults may not deliver the total dosage in children. Differences in the composition of body compartments and protein binding can alter the volume of drug distribution and, consequently, serum concentrations. In addition to pathophysiologic changes, there is evidence to suggest differences between a mature and immature brain. These differences include quantitative and qualitative responses to neurotransmitters. Hence, it is understandable why seizure semiology is different in children compared with adults. This constellation of factors contributes to the challenges of caring for children with epilepsy.

Optimal therapy of epilepsy by measuring serum concentration of antiepileptic drugs with least adverse effects

The study comprised 150 epileptic patients treated at the Institute of Neurology of the Clinical Centre Novi Sad. The optimal therapy with least adverse effects and seizures was achieved in patients in whom measurement of serum concentration of antiepileptic drugs was performed. Patients were divided into five groups with respect to the therapy they received: I--carbamazepane; II--valproic acid; III--polytherapy with phenobarbitone and diphenylhydantoin; IV--phenobarbitone and valproic acid; and V--phenobarbitone, valproic acid and carbamazepine. No adverse effects were recorded in over 60% of patients on monotherapy, 35% of patients who received two anticonvulsants, and 30% of patients who received three anticonvulsants. Significant correlation between drug dosage and blood drug concentration (r > 0.5) was found in polytherapy with phenobarbitone, carbamazepine and valproic acid (r = 0.66); and phenobarbitone and diphenylhydantoin (r = 0.53).

Upregulation of Multidrug Resistance Transporters in the Epileptic Brain.

Limbic Seizures Induce P-glycoprotein in Rodent Brain: Functional Implications for Pharmacoresistance Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, Aliprandi M, Bagnati R, Fanelli R, D'Incalci M, Samanin R, Vezzani A J Neurosci 2002;22:5833–5839 The causes and mechanisms underlying multidrug resistance (MDR) in epilepsy are still elusive and may depend on inadequate drug concentration in crucial brain areas. We studied whether limbic seizures or anticonvulsant drug (AED) treatments in rodents enhance the brain expression of the MDR gene ( mdr) encoding a permeability glycoprotein (P-gp) involved in MDR to various cancer chemotherapeutic agents. We also investigated whether changes in P-gp levels affect AED concentrations in the brain. Mdr mRNA measured by reverse transcriptase–polymerase chain reaction (RT-PCR) increased by 85% on average in the mouse hippocampus 3–24 h after kainic acid–induced limbic seizures, returning to control levels by 72 h. Treatment with therapeutic doses of phenytoin (PHT) or carbamazepine (CBZ) for 7 days did not change mdr mRNA expression in the mouse hippocampus 1–72 h after the last drug administration. Six hours after seizures, the brain/plasma ratio of PHT was reduced by 30%, and its extracellular concentration estimated by microdialysis was increased by twofold compared with control mice. Knockout mice (mdr1a/b_/_) lacking P-gp protein showed a 46% increase in PHT concentrations in the hippocampus 1 and 4 h after injection compared with wild-type mice. A significant 23% increase was found in the cerebellum at 1 h and in the cortex at 4 h. CBZ concentrations were measurable in the hippocampus at 3 h in mdr1a/b_/_mice, whereas they were undetectable at the same interval in wild-type mice. In rats having spontaneous seizures 3 months after electrically induced status epilepticus, mdr1 mRNA levels were enhanced by 1.8-fold and fivefold on average in the hippocampus and entorhinal cortex, respectively. Thus changes in P-gp mRNA levels occur in limbic areas after both acute and chronic epileptic activity. P-gp alterations significantly affect AED concentrations in the brain, suggesting that seizure-induced mdr mRNA expression contributes to MDR in epilepsy. Overexpression of Multiple Drug Resistance Genes in Endothelial Cells from Patients with Refractory Epilepsy Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg MR, Bengez L, Janigro D Epilepsia 2001;42:1501–1506 Purpose It has been suggested that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). To test this hypothesis further, we measured multiple drug resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue. Methods cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data. Results We found overexpression of selected MDR and significantly higher P-glycoprotein levels in “epileptic” versus “control” ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin resistance-associated protein (hCRA-α) also was Conclusions Complex MDR expression changes may play a role in AED pharmacoresistance by altering the permeability of AEDs across the BBB. overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue.

The Role of Drug-resistance Proteins in Medically Refractory Epilepsy.

Drug Resistance in Epilepsy: Expression of Drug-resistance Proteins in Common Causes of Refractory Epilepsy Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Brain 2002;125(Pt 1):22–31 Epilepsy is resistant to drug treatment in about one third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Among the various resistance mechanisms, overexpression of drug-resistance proteins, such as multidrug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance–associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 also may be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurons, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumors (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases), and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumor nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression also was noted in dysplastic neurons. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein–positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 also may do so. The overexpression of these drug-resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins reduce the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs. P-Glycoprotein and Multidrug Resistance–associated Protein Are Involved in the Regulation of Extracellular Levels of the Major Antiepileptic Drug Carbamazepine in the Brain Potschka H, Fedrowitz M, Loscher W. Neuroreport 2001;12:3557–3560 Despite considerable advances in the pharmacotherapy of epilepsy, about 30% of epilepsy patients are refractory to antiepileptic drugs (AEDs). In most cases, a patient who is resistant to one major AED also is refractory to other AEDs, although these drugs act by different mechanisms. The mechanisms that lead to drug resistance in epilepsy are not known. Recently, overexpression of multidrug transporters, such as P-glycoprotein (PGP) and multidrug resistance–associated protein (MRP), has been reported in surgically resected epileptogenic human brain tissue and suggested to contribute to the drug resistance of epilepsy. However, it is not known to what extent multidrug transporters such as PGP or MRP are involved in transport of AEDs. In the present study, we used in vivo microdialysis in rats to study whether the concentration of carbamazepine in the extracellular fluid of the cerebral cortex can be enhanced by inhibition of PGP or MRP, using the PGP inhibitor verapamil and the MRP inhibitor probenecid. Local perfusion with verapamil or probenecid via the microdialysis probe increased the extracellular concentration of carbamazepine. The data indicate that both PGP and MRP participate in the regulation of extracellular brain concentrations of the major AED carbamazepine.