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Objective Approximately 30% of patients with epilepsy are refractory to existing antiseizure drugs (ASDs). Given that the properties of the central nervous systems of these patients are likely to be altered due to their epilepsy, tissues from rodents that have undergone epileptogenesis might provide a therapeutically relevant disease substrate for identifying compounds capable of attenuating pharmacoresistant seizures. To facilitate the development of such a model, this study describes the effects of classical glutamate receptor antagonists and 20 ASDs on recurrent epileptiform discharges (REDs) in brain slices derived from the kainate-induced status epilepticus model of temporal lobe epilepsy (KA-rats). Methods Horizontal brain slices containing the medial entorhinal cortex (mEC) were prepared from KA-rats, and REDs were recorded from the superficial layers. 6-cyano-7-nitroquinoxaline-2,3-dione, (2R)-amino-5-phosphonovaleric acid, tetrodotoxin, or ASDs were bath applied for 20 minutes. Concentration-dependent effects and half maximal effective concentration values were determined for RED duration, frequency, and amplitude. Results ASDs targeting sodium and potassium channels (carbamazepine, eslicarbazepine, ezogabine, lamotrigine, lacosamide, phenytoin, and rufinamide) attenuated REDs at concentrations near their average therapeutic plasma concentrations. γ-aminobutyric acid (GABA)ergic synaptic transmission-modulating ASDs (clobazam, midazolam, phenobarbital, stiripentol, tiagabine, and vigabatrin) attenuated REDs only at higher concentrations and, in some cases, prolonged RED durations. ASDs with other/mixed mechanisms of action (bumetanide, ethosuximide, felbamate, gabapentin, levetiracetam, topiramate, and valproate) and glutamate receptor antagonists weakly or incompletely inhibited RED frequency, increased RED duration, or had no significant effects. Significance Taken together, these data suggest that epileptiform activity recorded from the superficial layers of the mEC in slices obtained from KA-rats is differentially sensitive to existing ASDs. The different sensitivities of REDs to these ASDs may reflect persistent molecular, cellular, and/or network-level changes resulting from disease. These data are expected to serve as a foundation upon which future therapeutics may be differentiated and assessed for potentially translatable efficacy in patients with refractory epilepsy.

Data on the effects of antiepileptic drugs on the immune system are frequently inconsistent and sometimes conflicting because the effects of drugs cannot be separated from those of seizures, first-generation drugs have been most intensively investigated, the patient's genetic background, the mechanism of action and the pharmacokinetic profile of AEDs and the concurrent use of immunosuppressant drugs may act as confounders. Valproate, carbamazepine, phenytoin, vigabatrin, levetiracetam, and diazepam have been found to modulate the immune system activity by affecting humoral and cellular immunity. AEDs are associated with pharmacokinetic interactions (most frequently occurring with carbamazepine, phenytoin, phenobarbital and valproate). Hepatic metabolism is the primary site of interaction for both AEDs and immunotherapies (ACTH, dexamethasone, hydrocortisone, methylprednisolone, cyclophosphamide, methotrexate, rituximab), which entail induction or inhibition of drug effects. However, the clinical importance of these drug interactions is still far from defined. An important adverse effect of the action of AEDs on the immune system is antiepileptic hypersensitivity syndrome (AHS), a life-threatening, idiosyncratic cutaneous reaction to aromatic AEDs resulting in end organ damage. Phenytoin, carbamazepine, phenobarbital, lamotrigine, oxcarbazepine, felbamate, and zonisamide have been implicated. The pathogenic mechanisms of AHS are incompletely understood.

Summary Purpose: To determine the effects of long-term use of felbamate (FBM) on weight, complete blood count, liver function tests, and seizure control, and also to determine the effect of age on FBM clearance. Methods: A computerized prospective database was used to identify all subjects who had FBM listed as one of their antiepileptic drugs (AEDs) during their most recent clinic visit. Medical records from each patient were then reviewed for inclusion criteria [treatment >2 years, FBM initiated at the study clinic, data for pre-FBM (Time-1; T1), one-year exposure to FBM (Time-2; T2), and the latest visit (Time-3; T3)]. Clinical information was abstracted from clinic charts. Results: Seventy-seven patients (F = 41, M = 36; ages 10–69 years) met entry criteria. Mean treatment time was 7.4 years, with the longest 20.3 years. Significant weight loss (mean 5.1 kg; p

Weight gain or loss is not an integral part of epilepsy although a sedentary lifestyle can contribute to weight gain. Pharmacological treatment for epilepsy may be associated with substantial weight changes that may increase morbidity and impair adherence to the treatment regimen. Antiepileptic drugs (AEDs) associated with weight loss are felbamate, topiramate, and zonisamide. AEDs associated with weight gain are gabapentin, pregabalin, valproic acid, and vigabatrin and possibly, carbamazepine. Weight neutral AEDs are lamotrigine, levetiracetam, and phenytoin. In clinical practice it is critical to weigh patients regularly and AED selection should be based on each patient's profile without sacrificing therapeutic efficacy.

Summary: Purpose: Polytherapy with two or more antiepileptic drugs (AEDs) is generally required for approximately 30% of patients with epilepsy, who do not respond satisfactorily to monotherapy. The potential usefulness of AED combinations, producing synergistic anticonvulsant efficacy and minimal adverse effects, is therefore of significant importance. The present study sought to ascertain the potential usefulness of levetiracetam (LEV) and felbamate (FBM) in combination in the mouse maximal electroshock (MES)-induced seizure model. Methods: The anticonvulsant interaction profile between LEV and FBM in the mouse MES-induced seizure model was determined using type II isobolographic analysis. Acute adverse effects (motor performance) were ascertained by use of the chimney test. LEV and FBM brain concentrations were measured by HPLC in order to determine any pharmacokinetic contribution to the observed antiseizure effect. Results: LEV in combination with FBM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, were supraadditive, whereas at the fixed ratio of 1:4, additivity was observed in the mouse MES model. Furthermore, none of the investigated combinations altered motor performance in the chimney test. Brain FBM concentrations were unaffected by concomitant LEV administration. In contrast, FBM significantly increased LEV brain concentrations. Conclusions: LEV in combination with FBM was associated with pharmacodynamic supraadditivity in the MES test. However, this anticonvulsant supraadditivity was associated with a concurrent increase in brain LEV concentrations indicating a pharmacokinetic contribution to the observed pharmacodynamic interaction between LEV and FBM.

Summary: Purpose: The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis. Methods: Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established. Results: With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task. Conclusions: LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.

Summary: Purpose: We developed a new in vitro preparation of immature rats, in which intact corticohippocampal formations (CHFs) depleted in magnesium ions become progressively epileptic. The better to characterize this model, we examined the effects of 14 antiepileptic drugs (AEDs) currently used in clinical practice. Methods: Recurrent ictal-like seizures (ILEs, four per hour) were generated in intact CHFs of P7–8 rats, and extracellular recordings were performed in the hippocampus and neocortex. AEDs were applied at clinically relevant concentrations (at least two), during 30 min after the third ILE. Their ability to prevent or to delay the next ILE was examined. Results: Valproic acid and benzodiazepines (clobazam and midazolam) but also phenobarbital and levetiracetam prevent the occurrence of seizures. In contrast, usual concentrations of carbamazepine (CBZ), phenytoin, vigabatrin, tiagabine, gabapentin, lamotrigine (LTG), topiramate, felbamate, and ethosuximide did not suppress ILEs. In addition, LTG and CBZ aggravate seizures in one third of the cases. Conclusions: This intact in vitro preparation in immature animals appears to be quite resistant to most AEDs. Blockade of seizures was achieved with drugs acting mainly at the γ-aminobutyric acid (GABA)A-receptor site but not with those that increase the amount of GABA. Drugs with a broad spectrum of activity are efficient but not those preferentially used in partial seizures or absences. We suggest that this preparation may correspond to a model of epilepsy with generalized convulsive seizures and could be helpful to develop new AEDs for refractory infantile epilepsies.

Women with epilepsy (WWE) have a risk of bearing children with congenital malformations that is approximately twice that of the general population. Most antiepileptic drugs (AEDs) have been associated with such risk. Valproate and carbamazepine have been associated specifically with the development of neural tube defects (NTDs), especially spina bifida. Other factors may contribute to the risk, including concomitant diseases such as diabetes mellitus, occupational exposure to teratogens, excessive prepregnancy weight, and various nutrient deficiencies. In the general population, maternal folate deficiency, in particular, has been linked with the development of NTDs, and periconceptional folate supplementation with a reduction of risk. It is unclear whether folate supplementation has a comparable protective effect for WWE. Data concerning the risk for congenital malformations associated with the newer AEDs (gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) are still limited. Several pregnancy registries for women taking AEDs have been established. Comprehensive postmarketing surveillance, regionally or nationally, might be the ideal method of monitoring medication safety, but government support for such an undertaking has for the most part been lacking. Despite uncertainty about the efficacy of periconceptional folate supplementation in WWE, these women should receive such supplementation at dosage levels recommended for the general population of women of childbearing age. Seizure control must not be neglected in a pregnant woman with epilepsy since seizures are associated with harm to the fetus as well as the mother. Risk may be minimized by using a single AED at the lowest effective dosage.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that appears in childhood. LGS is characterized by a slow spike-wave pattern on electroencephalogram (EEG), cognitive impairment, and multiple seizure types. This mixture of seizure types, along with the need to use more than one type of medication, makes LGS one of the most complicated epilepsies to treat successfully. Recent developments in approved therapies for the treatment of LGS offer physicians more options, but also make developing a treatment strategy that minimizes adverse events more challenging. There are currently 5 treatment options for LGS: felbamate, lamotrigine, topiramate, rufinamide, and clobazam, and several others that are used off-label, each of which has benefits and limitations. There are several factors that must be considered when determining which medication to use when treating patients with LGS, including efficacy, which is assessed by seizure frequency, tolerability, and the anticipated duration of treatment. In this article, data supporting current treatment options are discussed, and important considerations about the treatment of LGS are reviewed.

Summary: Purpose: To report a case of felbamate (FBM) urolithiasis. Methods: Urographic imaging [sonography, abdominal computed tomography (CT), intravenous pyelogram, voiding cystourethrogram] and urologic procedures (cystoscopy with lithotripsy, ureteral stent) to define and capture the stones. Stone identification was by infrared spectroscopy and gas chromatography/mass spectrometry. Results: A 15-year-old boy had painful hematuria, bilateral ureteral obstruction, and urinary retention. Kidney, bladder, and ureteral stones were found, and ureteral stent placement was required to relieve obstruction. The stone material was identified as FBM by chemical analysis. Stone formation ceased with discontinuation of FBM. Conclusions: FBM urolithiasis can occur, and possible contributory factors include high felbamate dosage, drug polypharmacy, and risk factors for forming stones of other types. FBM urolithiasis may be heralded by crystalluria.

This review focuses on the safety problems associated with antiepileptic drugs (AEDs) as revealed by laboratory testing and clinical examination. There are two classes of side effects: (a) common and mild and (b) rare and severe. Allergic reactions to AEDs are common and usually mild. However, on rare occasions, they can progress to more severe cutaneous disorders, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe allergic reactions to AEDs range from immune responses with fever to multiorgan dysfunction. Allergic rashes may be genetically or immunologically determined. Laboratory abnormalities produced by AEDs are common and mild, and include hepatic enzyme elevation associated with phenytoin and mild elevation in ammonia associated with valproate. Serious, although rare, idiosyncratic side effects, such as aplastic anemia, hepatotoxicity, and thrombocytopenia, have also occurred with AEDs. These reactions are largely confined to the "classic" AEDs. With the exception of felbamate, AEDs approved in the past decade have not been plagued by severe idiosyncratic reactions. Subtle endocrine abnormalities, including variations in thyroid function tests and bone metabolism, and the often subclinical effects on peripheral nerve conduction produced by phenytoin and carbamazepine, are also examined.

This article describes the mechanisms of idiosyncratic drug reactions (IDRs) and provides an analysis of potential methods for identifying patients at high risk for antiepileptic idiosyncratic drug reactions. IDRs may be caused by toxic metabolites, either directly or indirectly (by way of an immunologic response or a free radical-mediated process). Four methods to potentially identify patients at high risk for AED IDRs are discussed: development of an "at-risk" clinical profile for a particular AED: identification of biomarkers that measure the formation of a toxic metabolite by a previously unrecognized bioactivation pathway for a particular AED; identification of biomarkers indicating deficient detoxification abilities [e.g., deficient free radical scavenging enzyme activities or low calculated oxidative protection (COP) ratios 1 and 2]; and identification of at-risk genetic markers. Clinical profiles for patients receiving valproic acid (VPA), felbamate (FBM), and lamotrigine (LTG) and who are at risk for development of AED IDRs are presented. Patients with VPA IDRs have deficient erythrocyte glutathione peroxidase activity, low plasma selenium concentrations, low COP1 ratios, and low COP2 ratios compared with age-matched controls. Patients with FBM-associated aplastic anemia have deficient erythrocyte glutathione peroxidase, superoxide dismutase (SOD), and glutathione reductase activities compared with age-matched controls. Use of at-risk clinical profiles (for VPA, FBM, and LTG) and measurement of erythrocyte glutathione peroxidase activity, erythrocyte SOD activity, and calculation of COP1 and COP2 ratios (for VPA and FBM) are inexpensive, simple methods of identifying high-risk patients for IDRs. Research is needed to further characterize the mechanism of IDRs, to investigate the clinical utility of free radical-scavenging enzyme activity measurement and calculation of COP ratios for other AED IDRs, and to develop additional methods of identifying patients at high risk for AED IDRs.

Summary: Purpose: To examine the putative seizure-protective properties of felbarnate in an animal model of self-sustaining status epilepticus (SSSE). Methods: SSSE was induced by 30-min stimulation of the perforant path (PPS) through permanently implanted electrodes in free-running male adult Wistar rats. Felbarnate (FBM; 50, 100, and 200 mg/kg), dizepam (DZP; 10 mg/kg), or phenytoin (PHT; 50 mg/kg) were injected i.v. 10 min after SSSE induction. Electrographic manifestations of SSSE and the severity of SSSE-induced neuronal injury were analyzed. Results: Felbamate injected during the early stages of SSSE (10 min after the end of PPS), shortened the duration of seizures in a dose-dependent manner. Total time spent in seizures after FBM and 290 ± 251 min (50 mg/kg), 15.3 ± 9 min (100 mg/kg), and 7 ± 1 min (200 mg/kg), whereas control animals spent 410 ± 133 min seizing. This effect of FBM was stronger than that of DZP (10 mg/kg, 95 ± 22 min) and comparable to that of PHT (50 mg/kg, 6.3 ± 2.5 min). In the applied doses, FBM (200 mg/kg) was more effective than PHT (50 mg/kg) or DZP (10 mg/kg) in shortening seizure duration and decreasing spike frequency, when administered on the pleateau of SSSE (injection 40 min after the end of PPS). Anticonvulsant action of FBM was confirmed by milder neuronal injury compared with control animals. Conclusions: Felbamate, a clinically available AED with a moderate affinity for the glycine site of the NMDA receptor, displayed a potent seizure-protective effect in an animal model of SSSE. These results suggest that FBM might be useful when standard AEDs fail in the treatment of refractory cases of SE.

Because pharmacokinetics is a major determinant of the magnitude and duration of pharmacologic response, understanding the kinetic properties of the new antiepileptic drugs (AEDs) is essential for the correct use of these compounds in clinical practice. After oral administration, absorption is rapid and relatively efficient for the new AEDs, the most notable exception being gabapentin, whose bioavailability decreases with increasing dosage. None of the new AEDs is extensively bound to plasma proteins except for tiagabine, which is over 95% protein-bound. The route of elimination differs to an important extent from one compound to another, and elimination half-lives range from over 30 h for zonisamide to 5-7 h for gabapentin. For all drugs that are metabolized, half-life is shortened and clearance is increased when patients receive concomitant enzyme-inducing agents such as barbiturates, phenytoin, and carbamazepine. Lamotrigine metabolism is markedly inhibited by valproic acid, and felbamate may increase the serum levels of most other AEDs. Felbamate, topiramate, and oxcarbazepine may also reduce the efficacy of the contraceptive pill by stimulating its metabolism.

Summary: Purpose: This open-label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM). Methods: Ten subjects with epilepsy receiving PHT monotherapy were administered increasing doses of FBM (1,200, 1,800, 2,400–3,600 mg/day) at 2-week intervals. PHT doses were reduced by 20% on an individual basis when evidence of clinically significant intolerance was present. With intolerance, the PHT dose was reduced before the next incremental FBM dose. Blood samples were analyzed for FBM, PHT, and PHT metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH). Results: Total PHT plasma concentrations increased with coadministered FBM. PHT Cmax increased from 15.9 μg/ml at baseline to 20.9 μg/ml after 1,200 mg/day FBM and to 26.8 μg/ml after 1,800 mg/day FBM. Four subjects required a 20% PHT dose reduction after 1,800 mg/day FBM and six after the administration of 2,400 mg/day FBM. All subjects required further 20% PHT reductions before 3,600 mg/day FBM. FBM Cmax and AUCτ were reduced, and apparent clearance increased compared with data from FBM monotherapy. Conclusions: With the initiation of FBM therapy in subjects receiving PHT, the PHT dosage should be reduced by 20%. Further PHT dose reductions are likely to be necessary if the FBM dose is increased. The requirements for reductions in dose might be predicted by clinical signs of PHT intolerance.

Summary: Purpose: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropionaldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine. Methods: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population. Results: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured. Conclusions: This method demonstrated sufficient precision for the identification of patients exhibiting “abnormal” levels of atropaldehyde conjugates and may hold potential for patient monitoring.

The use of antiepileptic drugs (AEDs), singly and in combination, has been marked by variation among European countries and by a slow progress toward a standard of care that is still far from uniform. Phenobarbital, phenytoin, trimethadione, and primidone, given in various combinations, were the predominant agents used in the first half of this century. Prescribing habits differed among the Latin countries, the United Kingdom, and Scandinavia, based on local trends, divergent teaching philosophies of medical schools, and the medical specialty of the prescribing physician. The advent of carbamazepine and valproate, in the early 1960s, changed European prescribing habits. Despite early fears regarding bone marrow toxicity, carbamazepine was found to be superior for treatment of complex partial seizures. Valproate, when the proper therapeutic dosage was belatedly realized, was seen as a superior treatment for generalized and partial epilepsies. Both agents are now considered first-line treatments for these seizure types. The role of the benzodiazepines as adjunctive anticonvulsant therapy remains controversial because of concerns about neurotoxicity and patient tolerance. The number of AEDs marketed in Europe has grown dramatically in the past decade, with agents such as felbamate, gabapentin, lamotrigine, and tiagabine having been approved as either adjunctive or sole therapy. However, not all new agents are available in each European country, and some variation in prescribing persists.

Felbamate (FBM) was the first of the new antiepileptic drugs (AEDs) approved in the United States in 1993 with broad-spectrum efficacy against partial and generalized seizures of various types, and indicated for use as adjunctive and monotherapy. The identification of idiosyncratic aplastic anemia and hepatotoxicity, however, drastically curtailed its use. To update information concerning FBM and its idiosyncratic effects, case studies and literature reviews were undertaken. Thirty-four FBM-associated aplastic anemia patients have been reported, with 13 known fatalities. The overall FBM aplastic anemia risk is estimated at between 27 and 209 per million vs. 2 to 2.5 per million in the general population. Prior AED hypersensitivity, cytopenia, and immune disease significantly increase risk. FBM aplastic anemia has not been reported in children below the age of 13 years. Hepatic failure is much less common, occurring with an overall risk similar to that associated with valproate, but children below the age of 5 years have been affected. The recent identification of a reactive metabolite, atropaldehyde, and HLA studies suggest that high-risk patients can be identified. The efficacy profile of FBM should encourage further investigations to allow its better use, but at present FBM is not a first-line AED.

Hypersensitivity reactions to the aromatic antiepileptic drugs (AEDs) phenytoin (PHT) and carbamazepine (CBZ) appear to have an immune etiology. Current models of drug hypersensitivity center around the concept of drug bioactivation to reactive metabolites that irreversibly modify cellular proteins. These modified proteins are believed to initiate (or serve as targets of) an autoimmune-like attack on specific drug-modified proteins in target organs (e.g., liver, skin) of susceptible individuals. Consistent with this model, antibodies to drug-modified and native proteins have been identified in the sera of patients experiencing several drug hypersensitivity reactions. New models must incorporate an understanding of the mechanisms by which drug-modified proteins are processed and presented to the immune system in the appropriate context to culminate in the clinical manifestations of "hypersensitivity." Idiosyncratic toxicities associated with new AEDs, such as lamotrigine and felbamate, appear mechanistically distinct from PHT and CBZ hypersensitivity but may involve similar processes: bioactivation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T-cell immune effectors. The goal of research is to develop a "susceptibility profile" for identifying individuals at risk for these forms of drug toxicity.

Aggravation of focal epileptic seizures in adults is common after the antiepileptic drug (AED) therapy is initiated. Sometimes aggravation is mimicked by clustering of the seizures. Therefore, it is always necessary to analyze the patient's history and therapy carefully before drawing any conclusions. It is likely that a paradoxical aggravation of epileptic seizures can be attributed to the given AED and is sometimes, but only rarely, due to drug interactions.

Summary: Purpose: Felbamate (FBM) is a new antiepileptic drug (AED) that is often effective in seizure disorders refractory to other treatments; its use has been greatly restricted after cases of aplastic anemia were reported. To elucidate the putative association between FBM and aplastic anemia, we made a detailed evaluation of the first 31 reports. Methods: Hematologic review according to the criteria of the International Agranulocytosis and Aplastic Anemia Study (IAAAS) confirmed 23 cases (74%) as aplastic anemia; FBM was judged to be the only plausible cause for three; confounding (mostly by other drugs) was considered possible, but FBM remained the most likely cause for 11; and there was at least one other plausible cause for 9. Results: Using a denominator from sales data of 110,000 persons exposed and a numerator of the cases for which FBM was considered the only plausible cause, we established a lower limit of incidence of 27 cases of aplastic anemia per million users as compared with the general population rate of 2.0 per million per year. With all confirmed cases used as the numerator, the upper limit of incidence was 209 per million. The “most probable” incidence was estimated to be 127 per million. Conclusions: Intensive, systematic investigation can maximize the utility of case reports for assessing risks of newly released drugs. The present evaluation confirmed an association between FBM and aplastic anemia; however, confounding was significant for most cases and there was a tenfold range in the “best case” and “worst case” incidence estimates among users.

Summary: Purpose: Previous studies have demonstrated that felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate) at nontoxic doses exerts potent anticonvulsant activity in a variety of animal epilepsy or seizure models. We further characterized the anticonvulsant activity of FBM by using the kindling model of temporal lobe epilepsy (TLE). Methods: The experiments were performed in fully kindled rats. The anticonvulsant effect of FBM was assessed by determining seizure severity, after discharge (AD) duration and seizure duration either at the focal seizure threshold, or after supra threshold stimulation. In addition, the neurological performance of kindled rats after FBM administration was evaluated in the open field and by the rotorod test. Results: FBM at doses of 12.5–50 mg/kg, given intraperitoneally (i.p.) 60 min before testing, dose-dependently increased the AD threshold (ADT). The maximal effect was achieved after the highest dose tested and reached almost 600% of the control ADT. This dose of FBM significantly diminished other seizure parameters, e.g., seizure severity, seizure duration, and AD duration. When the rats were stimulated with suprathreshold current (500 μA) seizure severity was moderately but significantly reduced. No behavioral abnormalities were noted in kindled rats after administration of either of the doses. Conclusions: FBM potently increases the threshold for focal seizures and reduces seizure severity, seizure duration, and AD duration at doses that produce no adverse behavioral effects in amygdala-kindled rats. These data are thus compatible with clinical experience with FBM in TLE and substantiate that kindling is a good predictor of anticonvulsant activity against TLE.

Standard antiepileptic drugs (AEDs) are associated with a wide variety of acute and chronic adverse events and with many interactions with each other and with non-AEDs that complicate patient management. The safety and interaction profiles of the newer AEDs have also been intensively studied. Safety data are available for six of the newer AEDs, lamotrigine (LTG), vigabatrin (VGB), gabapentin (GBP), tiagabine (TGB), felbamate (FBM), and topiramate (TPM). The potential for the most recently developed AEDs for producing rare idiosyncratic reactions cannot be ascertained until additional patient exposures have been reported from careful postmarketing surveillance.

Summary: More than 50 million persons worldwide suffer from epilepsy, many of whom are refractory to treatment with standard antiepileptic drugs (AEDs). Fortunately, new AEDs commercialized since 1990 are improving the clinical outlook for many patients. Our growing understanding of anticonvulsant mechanisms and the relevance of preclinical animal studies to clinical antiepileptic activity have already contributed to the design of several new AEDs and should be increasingly beneficial to further efforts at drug development. Mechanisms have been identified for older AEDs [phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), barbiturates, benzodiazepines (BZDs), ethosuximide (ESM)] and newer AEDs [vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP) tiagabine (TGB), felbamate (FBM), topiramate (TPM)]. Several novel anticonvulsant mechanisms have recently been discovered. FBM appears to be active at the strychnine-insensitive glycine binding site of the NMDA receptor. TPM is active on the kainate/AMPA subtype of glu-tamate receptor and at a potentially novel site on the GABAA receptor. For several reasons, availability of a single AED with multiple mechanisms of action may be preferred over availability of multiple AEDs with single mechanisms of action. These reasons include ease of titration, lack of drug-drug interactions, and reduced potential for pharmacodynamic tolerance.

Novel antiepileptic drugs (AEDs) are thought to act on voltage-sensitive ion channels, on inhibitory neurotransmission or on excitatory neurotransmission. Two successful examples of rational AED design that potentiate GABA-mediated inhibition are vigabatrin (VGB) by irreversible inhibition of GABA-transaminase, and tiagabine (TGB) by blocking GABA uptake. Lamotrigine (LTG) prolongs inactivation of voltage-dependent sodium channels. The anticonvulsant action of remacemide (RCM) is probably largely due to blockade of NMDA receptors and prolonged inactivation of sodium channels induced by its desglycinated metabolite. Felbamate (FBM) apparently blocks NMDA receptors, potentiates GABA-mediated responses, blocks L-type calcium channels, and possibly also prolongs sodium channel inactivation. Similarly, topiramate (TPM) has multiple probable sites of action, including sodium channels, GABA receptors, and glutamate (AMPA) receptors. Gabapentin (GBP) apparently has a completely novel type of action, probably involving potentiation of GABA-mediated inhibition and possibly also inactivation of sodium channels. The therapeutic advantages of the novel AEDs are as yet only partially explained by our present understanding of their mechanisms of action.

Epilepsy is common in individuals who are mentally retarded and/or otherwise multiply handicapped. These patients often display several seizure types. Seizure control may be difficult and drug interactions common because of polytherapy. Cognitive, behavioral, affective, and motor problems in these patients often confound accurate diagnosis and effective management. Treatment often requires not only antiepileptic drugs (AEDs) but also psychoactive drugs and/or environmental and personal support. To minimize unwanted drug effects, therapeutic strategies should focus on the administration of the fewest possible drugs at the lowest effective dose. The new AEDs may be of special value at times in these populations because they offer potential for improved efficacy, but especially because many of them provide better safety profiles and fewer pharmacokinetic interactions with other drugs.

Antiepileptic drugs (AEDs) in broad use today have a number of pharmacokinetic liabilities, including a propensity for clinically meaningful drug interactions. Therefore, new AEDs with improved pharmacokinetic characteristics would be welcomed. The pharmacokinetic profiles of six newer AEDs--topiramate (TPM), gabapentin (GBP), vigabatrin (VGB), lamotrigine (LTG), oxcarbazepine (OCBZ), and felbamate--were reviewed. Some of these AEDs offer an improvement in one or more pharmacokinetic parameters compared with traditional AEDs, with TPM, GBP, VGB, and OCBZ demonstrating the most advantageous overall pharmacokinetic profiles.

The usefulness of felbamate (FBM) levels in managing epilepsy patients has not been determined. The purpose of the present study was to determine if FBM levels obtained at routine office visits correlated with side effects reported by patients. We determined FBM levels by high-pressure liquid chromatography (HPLC) of 46 epilepsy patient plasma specimens (41 patients) and assessed medication toxicity and seizure frequency by a questionnaire. Thirty-six patients were treated with other antiepileptic drugs (AEDs); concomitant AED levels not in ranges believed to cause toxicity. FBM levels ranged from 9 to 134 microgram/ml, and were divided into three groups for analysis, resulting in low-range (9-36 microgram/ml), midrange (37-54 microgram/ml), and high-level (44-134 microgram/ml) groups. Anorexia and complaints of severe side effects were reported significantly more often in the high-level group as compared with the low- and midrange groups. Significantly more patients in the high-level group (10/13) reported decreased seizure frequency, as compared with 12 of 30 patients in the low- and midrange groups combined. FBM levels correlated linearly with doses overall, but most closely in FBM monotherapy patients.

Studies of the newer antiepileptic drugs suggest that they are exciting additions with improved efficacy and a perhaps decreased toxicity in certain types of refractory childhood epilepsy. In some very rare syndromes only anecdotal reports exist and further study is needed. Issues of tolerability, long-term safety in very young children, and effects on learning, behavior and other cognitive functions must be balanced with the possibility of improved efficacy. Additional well-controlled studies taking into account both seizure types and epilepsy syndromes are very much needed in neonates, infants, school aged children and adolescents.

We studied the distribution of felbamate (FBM) in rat brain using a br ain imaging scanner to analyze thaw-mount autoradiographs. After intravenous injection of 14 C FBM in rats, the autoradiograph distribution of isotope labeling patterns in brain was captured on x-ray film. Densitometric differences on the x-ray film were converted into color-code variations representing the different concentrations of FBM in regions of the brain. We demonstrated that relatively uniform concentrations of FBM were detected throughout the brain. In all brain regions examined, there were no specifically high or low concentrations of FBM. We conclude that the FBM distributes uniformly.

Summary: We compared the anticonvulsant activity and neurotoxicity of 4-amino-N-(2,6–dimethyl-phenyl)phthalimide (ADD213063)with those of phenytoin (PHT), carbamazepine (CBZ), phenobarbital (PB), ethosuximide (ESM), valproate (VPA), and felbamate (FBM). Evaluation of anticonvulsant properties performed according to well-established procedures in rats and mice showed that ADD 213063 is most effective in protecting animals against maximal electroshock seizures (MES). This anti-MES activity is achieved with nontoxic doses, with the optimal effect recorded in rats dosed orally with anti-MES ED, and protective index (PI) values of 25.2 FmoYkg and >75, respectively. ADD 213063 protects to a lesser extent against seizures induced by subcutaneous (s.c.) picrotoxin and subcutaneous pentylenetetrazol(FTZ) in mice dosed intraperitoneally and orally, respectively. The profile of anticonvulsant action of ADD 213063 closely parallels that of CBZ.

As clinical experience with the pharmacokinetic properties and optimal dosing of the established antiepileptic drugs (AEDs) has increased, frequent monitoring of AED concentration in the blood may be less necessary than it was 15 to 25 years ago. Monitoring continues to be valuable at initiation of treatment, addition or removal of other interacting drugs, at the time of unexpected seizure breakthrough, or when symptoms suggest AED toxicity. Occasional determination to monitor compliance may also be appropriate. Blood level determinations of certain of the new, less familiar AEDs, including felbamate, lamotrigine, and oxcarbazapine, appear to be useful. However, new approaches are needed to monitor the efficacy and possible toxicity of other new AEDs for which the correlation between blood concentration of AED and clinical outcome is less clear. For administration of these AEDs, including gabapentin, tiagabine, and vigabatrin, other indirect measures, such as determination of gamma-aminobutyric acid (GABA) levels in the cerebrospinal fluid or by nuclear magnetic resonance spectroscopy, may prove useful. For monitoring compliance, alternate technologies, such as a medication-dispensing vial with an electronic memory chip, may be of clinical value. In the clinical management of patients with epilepsy, blood level monitoring plays an important role, but methods of using this monitoring have evolved with increased experience and the introduction of AEDs with new mechanisms of action.

Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. Phenytoin (PHT), carbamazepine (CBZ), and possibly valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing sodium-channel inactivation. Ethosuximide (ESM) and VPA reduce a low threshold (T-type) calcium-channel current. The mechanisms of action of the new AEDs are not fully established. Gabapentin (GBP) binds to a high-affinity site on neuronal membranes in a restricted regional distribution of the central nervous system. This binding site may be related to a possible active transport process of GBP into neurons; however, this has not been proven, and the mechanism of action of GBP remains uncertain. Lamotrigine (LTG) decreases sustained high-frequency repetitive firing of voltage-dependent sodium action potentials that may result in a preferential decreased release of presynaptic glutamate. The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.

Among some 14 new antiepileptic drugs (AEDs), those most extensively tested in humans include felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), vigabatrin (VGB), and zonisamide (ZNS). All are currently marketed in some but not all countries. Although no large, comparative studies on efficacy have been conducted, all of these new AEDs are effective in adult localization-related epilepsies, and some have activity in specific syndromes. Although these drugs all have some CNS side effects, especially when administered in combination with other AEDs, they also all have low toxicity profiles. The availability of AEDs with different mechanisms of action may facilitate rational polytherapy. FBM is not teratogenic in animals. Half-life of FBM in humans is 11-28 h. Daily FBM dosages are 15-45 mg/kg in children and 2,400-4,800 mg in adults. Side effects include insomnia and anorexia, with weight loss. FBM increases phenytoin (PHT) and valproate (VPA) concentrations, and FBM concentration may be affected by other drugs. It is available in the United States for treatment of Lennox-Gastaut syndrome and partial seizures in adults. GBP is very water soluble. Half-life of GBP in humans is 5-7 h and daily dosages range from 900 to 2,400 mg in adults. Few side effects have been observed. GBP is not metabolized by the liver and has no drug interactions. It is available in the United Kingdom and the United States. LTG has no teratogenicity in animal models. Half-life of LTG in humans depends on co-medication: with enzyme inducers it is 15-24 h, and with VPA it is approximately 60 h. LTG dosages are 100-600 mg/day in adults. LTG is available in Europe. OCBZ is rapidly metabolized to 10,11-dihydro-10-hydroxy-carbazepine (MHD), the active compound. Animal studies have shown similar efficacy but superior toxicity to carbamazepine (CBZ) in animal models. For MHD, half-life ranges from 10 to 15 h in patients. OCBZ dosages range from 300 to 1,800 mg/day. VGB is a potent, irreversible inhibitor of GABA transaminase which elevates GABA levels in the CNS. Daily dosages of 2,000-4,000 mg of VGB are needed in adults. Although intramyelinic edema has developed in rats and dogs, it has not yet presented in other mammals or humans. ZNS is a sulfonamide effective in animal models of epilepsy. Half-life of ZNS is 27-36 h. ZNS daily dosage is 400-600 mg. ZNS has been effective in some cases of Baltic myoclonic epilepsy.

Summary: Pediatric epileptology is very different from adult epileptology. Although some epileptic disorders occur in both children and adults (e.g., localization-related epilepsy with complex partial seizures and primary generalized epilepsy with tonic-clonic seizures), other disorders can be called the catastrophic epilepsies of childhood (e.g., infantile spasms and the Lennox-Gastaut syndrome). They occur, or at least begin, exclusively in childhood and are often associated with mental retardation. Many of these pediatric disorders are notoriously unresponsive to currently available antiepileptic drugs (AEDs). Although there are undoubtedly many reasons for this, one possible explanation is that the methods used to screen potential AEDs use animal models of adult epilepsy. No screening program uses an animal model of seizures that begin during development and lead to functional decline.

Felbamate (FBM) is a new antiepileptic drug (AED) that has been evaluated in partial seizures and in the Lennox-Gastaut syndrome (LGS). When tested against placebo in an add-on, randomized, double-blind trial in 73 children with LGS, FBM significantly reduced the frequencies of astatic (atonic) seizures and generalized tonic-clonic seizures plus total seizure counts. In addition, FBM-treated subjects improved significantly on a parent-rated global evaluation and had fewer injuries. Overall, approximately 50% of subjects experienced a 50% or greater reduction in total seizure frequency and a dose-response relationship was apparent. The improvement that occurred in the double-blind study has been sustained for at least 12 months in subsequent open-label follow-up studies. In the first month of FBM treatment, 62% of the subjects who had previously received placebo had a reduction in total seizure frequency of > 50%. By the 12-month follow-up point, approximately half of the patients had a 50% reduction in total seizure count. Astatic seizures responded even better, with two-thirds of patients having a reduction of > 50% in astatic seizure frequency after 12 months of treatment. Based on adverse experience reports thus far, FBM appears to be well tolerated. FBM is the first drug to be shown effective in the LGS in randomized controlled trials. Although few subjects with LGS became seizure free, the frequency of the most severe seizure types decreased and the patients' global functioning improved.

Felbamate (FBM) is a new antiepileptic drug (AED) that has been tested in open and controlled studies in patients with therapy-refractory partial-onset seizures. Proof of efficacy is based on results of five controlled studies (three with polytherapy and two with monotherapy). In two of the three polytherapy studies, a classic placebo crossover design was used. The third study used a novel design evaluating the efficacy of FBM in a placebo-controlled parallel design in patients completing an evaluation for epilepsy surgery. The primary efficacy variable in this study was the number of patients who experienced a fourth seizure before the end of the study. Forty-six percent of patients randomized to FBM stopped treatment prematurely because of a fourth seizure compared with 88% randomized to placebo. Two studies investigating the efficacy in monotherapy were performed. Both studies used an identical trial design comparing FBM with a low dosage of valproate (VPA). The efficacy of FBM was found to be superior to the low-dosage VPA for both studies. Open long-term follow-up studies have confirmed the long-term efficacy of FBM for up to 12 months. Overall, FBM was well tolerated in both poly- and monotherapy.

Antiepileptic drug (AED) development has been generally difficult owing to many factors: regulatory requirements for demonstration of efficacy and safety, subject availability, traditional trial designs, and physicians' beliefs about epilepsy and its treatment. The U.S. Food and Drug Administration (FDA) regulations require a new drug to be shown safe and effective for its intended use before it can be marketed. The unambiguous proof required is a formidable hurdle for AED development. We report a recent clinical development plan highlighting innovations in clinical trial design that have addressed these requirements, discuss alternative endpoints, and compare the results of various trial designs at various stages of development. This model clinical development plan includes trials relevant to all three clinically relevant contexts in which an AED might be used: as an adjunct to an existing regimen, as a substitution for much of an existing AED regimen, and as monotherapy.

Summary: The anticonvulsant effects of felbamate (FBM) alone or in combination with phenytoin (PHT), carbamazepine (CBZ), valproate (VPA), or phenobarbital (PB) were investigated against maximal electroshock (MES) seizures in mice. Nonprotective doses of the prototype antiepileptic drugs (AEDs) enhanced the protective effects of FBM against electrically induced seizures, as shown by significant reduction of FBM ED50 values. Toxicity as determined by rotorod test was not significantly potentiated, however, and the protective index (PI = TD50/ED50) of FBM was increased by >100% for each AED interaction. The increase in anticonvulsant potency of FBM after its combination with nonprotective doses of AEDs could not be accounted for by a pharmacokinetic mechanism. ReSUMe L'effet anticonvulsivant du Felbamate (FBM) seul ou en association avec la phenytoine, la carbamazepine, le valproate ou le phenobarbital a eteetudie dans le modele des crises apres electrochoc maximal (MES) chez la souris. Des doses non protectrices des antiepileptiques classiques (MAE) ont augmente les effets protecteurs du FBM contre les crises induites electriquement, ce qui a ete demontre par une reduction significative des valeurs ED50 pour le FBM. Cependant la toxicite, demontree par le test du rotorod, n'a pas ete significativement augrnentee, et l'index de protection (TD50/ED50) du FBM a eteeleve par plus de 100% par chacun des MAE associes. L'augmentation de la puissance anticonvulsivante du FBM lors d'une association avec des doses non protectrices des MAE classiques ne peut etre expliquee par un mecanisme pharmacocinetique.

The brain uptake index (BUI) method of Oldendorf was used to examine blood-brain barrier (BBB) drug transport in mice, rats, and rabbits; felbamate (FBM) extraction (E) in a single transcapillary passage was 5-20%, and drug uptake in rat brain was not concentration-dependent. Like diazepam, FBM was retained in mouse brain. To ensure that radioactivity measurements reflected the disposition of parent drug and not some metabolite, extracts of mouse brain were prepared for further analysis. No FBM metabolites were detected in brain 5 min after administration: In silica gel thin-layer chromatography (TLC), a single [14C]FBM peak was detected--Rf = 0.504 (70:30 acetone:hexane). Confirmatory high-performance liquid chromatography (HPLC) separations [30% methanol, 1.3 ml/min, C18 column, ultraviolet (UV) detection 254 nm] indicated a single peak containing greater than 93% of the radioactivity in the FBM fraction (12-min retention time). In a single transit through the liver (a nonbarrier tissue with fenestrated capillaries), FBM E was 82%. The octanol:buffered saline partition coefficient of FBM was (log PFBM =) 0.54 +/- 0.01. Thus, lipid-mediated BBB penetration of FBM is similar to that of phenytoin (PHT) and phenobarbital (PB). Plasma proteins do not affect FBM entry to the brain: neither human serum, nor bovine or human serum albumin (BSA, HSA), nor human alpha 1 acid glycoprotein (orosomucoid) significantly modified BBB FBM extraction. Erythrocyte-borne FBM may also dissociate and gain access to the brain in a single transcapillary passage. Differences between newborn and adult rabbit BBB FBM extraction and between different anesthetic agents are attributable to cerebral blood flow (CBF) rates. The permeability-surface area products (PS = [CBF].[E]) for FBM in rats, rabbits, and mice were 0.09, 0.16 and 0.30 ml/min/g, respectively. Preliminary autoradiographic analyses of frozen brain sections suggest that [14C]FBM distributes relatively uniformly throughout the brain and that minor variations apparently are a function of differing CBF rates.

We review recent advances in our understanding and treatment of status epilepticus (SE). Repeated seizures cause an internalization of gamma-aminobutyric acid (GABA)(A) receptors, together with a movement of N-methyl-d-aspartate (NMDA) receptors to the synapse. As a result, the response of experimental SE to treatment with GABAergic drugs (but not with NMDA antagonists) fades with increasing seizure duration. Prehospital treatment, which acts before these changes are established, is finding increased acceptance, and solid evidence of its efficacy is available, particularly in children. Rational polypharmacy aims at multiple receptors or ion channels to increase inhibition and simultaneously reduce excitation. Combining GABA(A) agonists with NMDA antagonists and with agents acting at other sites is successful in treating experimental SE, and in reducing SE-induced brain damage and epileptogenesis. The relevance of these experimental data to clinical SE is actively debated. Valproate and levetiracetam have recently become available for intravenous use, and the use of ketamine and of other agents (topiramate, felbamate, etc.) have seen renewed interest. A rapidly increasing but largely anecdotal body of literature reports success in seizure control at the price of relatively few complications with the clinical use of those agents in refractory SE.

We prospectively investigated drug-induced headaches (HA) among 60 epileptic patients receiving felbamate (FBM). Twenty patients (33%) experienced HA. HA was pounding in 11 (55%), steady in 9 (45%), moderate or severe in 19 (95%), occurred at least once a week in all patients, and was relieved by nonnarcotic analgesics in 14 (70%). Mean duration on FBM before HA onset was 19 days. HA occurred with higher FBM doses and was relieved in 8 of 13 patients (62%) with FBM dose reduction. FBM was discontinued in most cases because of risks of anemia or hepatitis; not because of HA. Other side effects included insomnia (25%), gastrointestinal symptoms (27%), and agitation or restlessness (23%). HA is a common dose-related complication of FBM, occurs early after initiation of FBM treatment, and is relieved by dose reduction.

Summary: Purpose: Despite possibility of idiosyncratic reaction development, felbamate (FBM) is recommended in Lennox–Gastaut syndrome and partial refractory epilepsy. The aim of this study was to evaluate the profile of interactions between FBM and four conventional antiepileptic drugs (AEDs): clonazepam (CZP), ethosuximide (ESM), phenobarbital (PB), and valproate (VPA), in pentylenetetrazole (PTZ)-induced convulsions in mice, a model of myoclonic seizures in humans. Methods: Data obtained from PTZ-evoked seizures were compared by use of two basic procedures, the subthreshold method and isobolographic analysis. Results of the chimney test (evaluating motor coordination) also were elaborated isobolographically. Thus it was possible to determine both median toxic dose (TD50) and protective index (PI) for each drug combination. Results: FBM reduced the clonic seizure activity [with an ED50 of 9.7 mg/kg; TD50, 439.1 mg/kg; and PI, 45.3]. FBM at the dose of 10 mg/kg, but not 7.5 mg/kg, significantly reduced PTZ-induced convulsions in mice. In the subthreshold method, FBM (7.5 mg/kg) did not affect the protective activity of conventional AEDs used in the study. However, when applied at 10 mg/kg, it enhanced the protective activity of PB and ESM, but not that of VPA or CZP. The nature of these interactions could not be precisely estimated with this method. The exact profile of drug interactions was determined with the use of isobolography. In terms of seizure inhibition, antagonism was found between FBM and VPA applied at the fixed-dose ratio of 3:1. Synergy was detected between FBM and PB (1:3). Combinations of FBM with VPA (1:3, 1:1), PB (1:1, 3:1), and ESM or CZP (1:3, 1:1, 3:1) led to additive interactions. As regards motor impairment, the combinations of FBM with VPA (1:3) or CZP (1:1, 3:1) were synergistic. Remaining combinations exhibited pure additivity. Pharmacokinetic events may influence FBM/ESM and FBM/CZP interactions, because FBM lowered the brain concentration of ESM and increased that of CZP. Conclusions: The profitable benefit index was found only for the combination of FBM with PB (1:3). Conversely, the combinations of FBM with either VPA (1:3) or CZP (1:1, 3:1) do not seem promising for the therapy of refractory myoclonic convulsions. Isobolographic analysis provides more reliable clues to be considered by the clinicians willing to introduce AED combinations for the therapy of epilepsy.

Treatment of the catastrophic epilepsies [infantile spasms (IS), Lennox-Gastaut syndrome (LGS), and progressive myoclonic epilepsy (PME)] remains a challenge to clinicians. For IS, adrenocorticotropic hormone has traditionally been the drug of choice in the United States but may be associated with serious side effects in some patients. Vigabatrin has shown promise in treating IS patients, particularly those with tuberous sclerosis. However, the drug is associated with visual field loss and is not commercially available in the United States. Newer antiepilepsy drugs (AEDs), such as zonisamide, topiramate (TPM), and lamotrigine (LTG), may be useful in patients with IS. Although LTG, TPM, and felbamate are approved in the United States for the treatment of LGS, the overall effectiveness of therapy in patients with LGS is poor. For PME, valproate is a first-line treatment. Zonisamide and levetiracetam also show promise. Supplementation with certain cofactors to correct deficiencies and increase mitochondrial function may be useful in some patients with PME, but response to such therapy is not well documented. Advances in our understanding of the etiologies, mechanisms, and genetics underlying the catastrophic epilepsies may facilitate more effective pharmacologic interventions.

Summary: Purpose: The need for an efficacious treatment of patients with intractable seizures is urgent and pressing, because ∼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. Methods: 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. Results: 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. Conclusions: 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.

Summary: Purpose: 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. Methods: 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. Results: 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. Conclusions: In this present study, the microdialysis results gave no evidence that ABCC2 function modulates entry of CBZ, LTG, and FBM into the CNS of naive 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.

Summary: Purpose: Talampanel (LY300164), a potent and selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-receptor antagonist, is a potential new antiepileptic drug (AED). This study examines the single- and multiple-dose pharmacokinetics, safety, and tolerability of talampanel in patients with intractable epilepsy and assesses the potential for pharmacokinetic interaction. Methods: Eleven of 14 patients entered into the study completed. Fourteen patients were evaluated for safety, 13 patients were used in the single-dose, and 11 patients in the multiple-dose pharmacokinetic analysis. Each patient initially received a single 35-mg dose of talampanel followed by the measurement of pharmacokinetic profiles. A 21-day t.i.d. dosing regimen was then determined for each patient based on his or her initial pharmacokinetic profile. Adverse events were recorded by patients or their carers. Results: After oral ingestion, talampanel was rapidly absorbed, with maximal plasma concentrations achieved within 1–3 h. Talampanel concentrations in patients taking enzyme-inducing AEDs were 50% lower than those seen in healthy volunteers. Mean talampanel t1/2 values were 3.0 h compared with 4.2 h in healthy volunteers. After multiple-dose and steady-state, talampanel t1/2 values were increased to 5.6 h Talampanel and valproic acid (VPA) appear to inhibit each other's metabolism mutually. Talampanel had no effect on plasma concentrations of other AEDs. Multiple-dose talampanel administration was associated with nonlinear pharmacokinetics. No serious adverse events were reported; the most frequently reported being dizziness, ataxia, drowsiness, and headaches Conclusions: Talampanel dosing strategies may be reliant on concomitant AED medication, as enzyme-inducing AEDs enhance, whereas VPA inhibits its metabolism. Talampanel was well tolerated, although adverse events occurred at lower doses compared with those in healthy subjects, probably because of the additive effect of concomitant AEDs.