Effects Of Felbamate Research Articles

Felbamate produces antidepressant-like actions in the chronic unpredictable mild stress and chronic social defeat stress models of depression.

Felbamate is an anticonvulsant used in the treatment of epilepsy. In this study, we investigated the antidepressant-like actions of felbamate in mice. The effects of felbamate were first assessed using the forced swimming test (FST) and tail suspension test (TST), and then investigated in the chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models of depression. The changes in the hippocampal brain-derived neurotrophic factor (BDNF) signaling cascade after chronic stress and felbamate treatment were also examined. It was found that felbamate exhibited antidepressant-like activities in the FST and TST without affecting the locomotor activity of mice. Felbamate was also effective in both the CUMS and CSDS models of depression. Moreover, felbamate administration fully restored the decreased hippocampal BDNF signaling pathway in both the CUMS-stressed and CSDS-stressed mice. Collectively, felbamate has antidepressant-like actions in mice involving the hippocampal BDNF system.

The effects of felbamate on appetitive and aversive instrumental learning in adult rats

Antiepileptic medications are the frontline treatment for seizure conditions but are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin-, carbamazepine-, and valproate-treated rats. In the present experiment, the effects of felbamate (FBM) have been compared to water-treated controls (controls) using the same instrumental training tasks employed here. Rats treated with FBM displayed a deficit in acquiring a tone-signaled avoidance response, relative to controls, but this was true only if they had no prior appetitive experience. Terminal avoidance behavior was equivalent to healthy controls. In contrast, the FBM-treated rats showed enhanced acquisition of the avoidance response relative to controls when given the benefit of prior experience in the appetitive condition. Relative to animals treated with phenytoin, carbamazepine, or valproate, FBM-treated rats showed the lowest overall pattern of deficits using these instrumental learning tasks. While FBM treatment has been severely restricted because of rather low risks of serious medical side effects, we suggest that the risks are not substantially higher than those shown to exist for phenytoin, carbamazepine, or valproate. As psychologists, we further suggest that negative cognitive deficits associated with these various drugs, along with their quality-of-life costs, are of relevance in the design of treatment strategies for individuals with seizure disorders.

P.1.099 Antidepressant-like effects of felbamate on locomotor behaviour and leukocyte phagocytosis in rats

To examine potential antidepressant effects of felbamate rats with bilateral lesion of the olfactory bulb (OB rats) were used in the present study. This animal model resembles behavioural, endocrine and immune changes found in human depression. Repeated felbamate treatment (240 mg/kg, orally, for 10 days) effects on locomotor behaviour (ambulation) in an open field test, and on leukocyte phagocytosis were studied in both sham-operated and bulbectomized rats. Felbamate elicited a significant decrease of the previously hyperactive ambulation of the OB rats after 10 days of medication (240 mg/kg/day, orally), while no marked changes were observed in sham-operated animals. On the day 10 of the felbamate treatment, there was no significant difference in locomotor activity of the OB and the sham-operated rats. Significantly suppressed leukocyte phagocytic activity recorded in OB rats was disinhibited in those treated repeatedly with felbamate while the drug did not alter phagocytosis of leukocytes in sham-operated group. Results of both these experiments indicate hypothesized antidepressant activity of felbamate.

Changes in somatosensory evoked potentials following forebrain ischemia in the gerbils: effects of felbamate.

Somatosensory evoked potentials (SEPs) as well as change following transient cerebral ischemia in the gerbil were characterized in this study. SEPs were measured in each gerbil before ischemia (day -1), during ischemia, 10 min, 2, 4, 8, 24, 48 h and 8 days after recirculation. During bilateral carotid occlusion, SEP amplitude was dramatically reduced and central conduction time was significantly increased. During recirculation these values showed an improvement when compared to ischemic but not to control values. Moreover at 8 days of recirculation they were still statistically different from control values. Felbamate administration at the dose of 150 mg kg(-1), immediately after recirculation was shown to ameliorate neurophysiological recovery following cerebral ischemia.

An electrophysiological analysis of the protective effects of felbamate, lamotrigine, and lidocaine on the functional recovery from in vitro ischemia in rat neocortical slices

An electrophysiological analysis of the protective effects of felbamate, lamotrigine, and lidocaine on the functional recovery from in vitro ischemia in rat neocortical slices

Changes of the Eeg Paroxysmal Pattern During Felbamate Therapy in Lennox-Gastaut Syndrome: A Case Report

We report a case of a 43-year old woman with Lennox-Gastaut syndrome who exhibited atypical absence seizures, atonic seizures and generalized toniclonic seizures which were not controlled by antiepileptic drug (AED) treatment. Because of this, felbamate (FBM) (1800 mg per day) was progressively added to the pre-existent therapy.The patient underwent a 24-hour-video-EEG monitoring before and after 4 months of FBM therapy. Analysis of the video-EEG signal recorded during wakefulness revealed the presence of ictal activity represented by repetitive, bilateral, slow spike and wave bursts underlying atypical absence seizures; the ictal activity occurring during non-REM sleep was characterized by runs of bilateral, rapid, high-voltage spikes followed by slow spike and wave complexes corresponding to brief tonic seizures. FBM therapy induced disappearance of the EEG ictal slow, spike arid wave complexes leaving rather unaffected the runs of spikes. Computerized analysis of both the EEG background activity and the sleep structure displayed a better organization of the global cerebral rhythms under FBM treatment.Our findings suggest a selective effect of FBM on the ictal atypical spike and wave pattern. The differential effect of FBM on ictal patterns may be a reflection of a different action on the excitatory and inhibitory systems.

Antagonism of convulsions but failure to enhance GABA(A) receptor function by felbamate in mice tolerant to diazepam.

The transfer of tolerance between drugs may indicate a common mode of action. The development of cross-tolerance to the anticonvulsant effect of felbamate after long-term treatment of mice with diazepam, a positive modulator of gamma-aminobutyric acid (GABA)-mediated transmission, was therefore studied in order to clarify the mechanism of this action of felbamate. A challenge injection of felbamate, administered 36 h after the last dose of chronic diazepam treatment, antagonized convulsions elicited by administration of isoniazid. In contrast, felbamate had no effect on the isoniazid-induced increase in t-[35S]butylbicyclophosphorothionate binding to cerebral cortical membranes of diazepam-tolerant mice. These results suggest that the action of felbamate on GABAergic transmission is not required for the anticonvulsant effect of this drug. This conclusion is consistent with studies that have indicated that the antiepileptic activity of felbamate depends on its modulatory activity at excitatory amino acid receptors.

NEUROPROTECTIVE EFFECTS OF FELBAMATE ON GLOBAL ISCHAEMIA IN MONGOLIAN GERBILS

Felbamate is an antiepileptic drug whose action appears to occur mainly through an interaction with neurotransmission mediated by excitatory amino acids. We assessed its effectiveness in a model of transient global ischaemia in Mongolian gerbils. Dizocilpine (MK 801) was used for comparison. Treatment was given 10min after transient forebrain ischaemia which was performed by occluding both common carotid arteries for 10min. Felbamate (300mg/kg i.p.) increased the number of surviving neurons in the CA1, CA2 and CA3 hippocampal cells. In particular, the CA1 area had a significantly higher number of surviving pyramidal neurons than that of vehicle-treated animals (67±11 vs33±6 surviving neurons/mm; P<0.05). No significant difference in density of surviving neurons was observed between dizocilpine (3mg/kg i.p.) and vehicle (54±10 vs33±6 surviving neurons/mm). The EEG results indicated that the effect of felbamate, used alone, is the same in the ischaemic-vehicle group as non-ischaemic group. Our results show that felbamate exerts neuroprotective effects in a model of severe cerebral ischaemia.

Anticonvulsant effect of felbamate in the pentylenetetrazole kindling model of epilepsy in the rat.

The present study was designed to examine the ability of felbamate, a novel antiepileptic agent, to antagonize the increase in seizure severity (i.e., chemical kindling) produced by chronic treatment with initially subconvulsant doses of pentylenetetrazol (PTZ). Rats were treated with PTZ (30 mg/kg, i.p., three times a week) for 8 consecutive weeks. Two other groups of rats received felbamate (300 or 400 mg/kg, i.p.), 90 min before each dose of PTZ. Pretreatment with felbamate at either dose prevented the progression of rank of seizures during chronic treatment with PTZ. Thus, the mean seizure score by the end of the chronic treatment (0-5 scale) was 0 in vehicle treated controls, 3.3 in rats treated with PTZ alone, 1.5 in rats treated with PTZ plus felbamate (300 mg/kg, i.p.) and 0.9 in the group treated with PTZ plus felbamate (400 mg/kg, i.p.). Felbamate also antagonized the long-term increase in the sensitivity to the convulsant effects of GABA function inhibitors observed in PTZ-kindled rats. Thus, the administration of a challenge dose of isoniazid (120 mg/kg, s.c.), picrotoxin (1.5 mg/kg, i.p.) or PTZ itself (15 mg/kg, i.p.), 15 to 45 days after the end of the chronic treatment regimen, induced convulsions in > 80% of PTZ-kindled rats and in < 20% of rats treated with PTZ + felbamate (400 mg/kg). The results are discussed in terms of the multiple mechanisms that can contribute to the anticonvulsant action of felbamate in the PTZ kindling model of epilepsy.

Effects of felbamate, kynurenic acid derivatives and nmda antagonists on in vitro kainate-induced epileptiform activity

The effects of the novel anticonvulsant felbamate, which binds to the 5–7 dichlorokynurenic binding sites, were tested towards the CA1 epileptiform activity induced in rat hippocampal slices by kainic acid. The effects of the kynurenic acid derivatives 7-chlorokynurenic acid and 5–7-dichlorokynurenic acid and of the NMDA antagonists COS 19755, MK-801 and ketamine were also studied for comparison. Slice perfusion with 1 μM kainic acid produced within 30 min the development of an evoked CA1 epileptiform bursting made up by an increase in amplitude of the primary population spikes followed by the appearance of secondary epileptiform population spikes. Slice perfusion with CGS 19755 (100 μM) or MK-801 (100 μM) or ketamine (100 μM) failed to affect within 30 min the CA1 epileptiform activity due to kainic acid. On the contrary, slice perfusion with felbamate (1.3–1.6 mM) or 7-chlorokynurenic acid (100 μM) or 5–7-dichlorokynurenic acid (100 μM) produced within 30 min a significative (P < 0.05) decrease of the kainate-induced epileptiform bursting duration. The results indicate that felbamate and kynurenic acid derivatives but not NMDA antagonists present an inhibitory effect against the epileptiform activity due to kainic acid.

Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive

The effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive containing 30 micrograms ethinyl estradiol and 75 micrograms gestodene were assessed in a randomized, double-blind, placebo-controlled parallel-group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg/day felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration-time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during felbamate treatment.

Effect of Felbamate on the Plasma Protein Binding of Valproate

Coadministration of felbamate is known to raise plasma valproate concentrations. In an attempt to explain this interaction, the effect of felbamate (FBM) on the plasma protein binding of valproate (VPA) was investigated in vitro and in healthy subjects. In fresh drug-free human plasma spiked with 20.0, 60.0 and 100.0 mg NaVPA/L without and with 75.5 mg FBM/L, the overall mean (± SD) unbound VPA fraction was 10.3 ± 1.6% without and 11.7 ± 2.1% with FBM. Regression analysis, used to distinguish FBM effects on plasma protein binding from effects due to altered total VPA concentration (VPA shows concentrationdependent protein binding), indicated that the mean percentage unbound VPA rose by 1.44% (95% CI = 0.59 to 2.30%). In 12 subjects the mean (± SD) trough concentrations of total VPA in plasma rose from 21.0 ± 6.1 mg/L to 45.1 ± 9.5 mg/L (p < 0.01) when VPA was taken, and the overall mean (± SD) unbound VPA fraction increased from 10.5 ± 0.77% to 11.7 ± 1.17%. Regression analysis indicated that there was a mean increase of 0.68% (95% CI = 0.13 to 1.23%) in plasma-unbound VPA because of a direct effect of FBM on plasma protein binding, the remaining 0.5% increase being due to the altered VPA concentration. While FBM appears to displace VPA from plasma proteins, this interaction is small and unlikely to make any important contribution to the overall effect of adding FBM to VPA, although the total interaction between the two may be large enough to necessitate a lowering of VPA dose.

Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine

The effects of felbamate on the multiple dose pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine were assessed in a placebo-controlled, randomized, double-blind crossover study in 18 healthy male volunteers. Oxcarbazepine, 1200 mg/day, was administered on an open basis in combination with double-blind placebo or 2400 mg/day felbamate for two 10-day treatment periods separated by a 14-day washout period. Pharmacokinetic parameters of monohydroxyoxcarbazepine and dihydroxyoxcarbazepine were determined from plasma and urine samples obtained on the tenth day of each treatment period. Felbamate had no effect on monohydroxyoxcarbazepine plasma or urine pharmacokinetics compared with placebo, but it significantly increased values for dihydroxyoxcarbazepine maximum concentration and area under the curve from 0 to 12 hours, as well as urinary excretion of free and total dihydroxyoxcarbazepine. The mechanism that may account for the observations is the induction of oxidative metabolism of monohydroxyoxcarbazepine. Despite these changes, the relative amount of dihydroxyoxcarbazepine is small in comparison to monohydroxyoxcarbazepine, and antiepileptic activity is associated with monohydroxyoxcarbazepine rather than dihydroxyoxcarbazepine. Therefore we conclude that felbamate has no clinically relevant effects on the pharmacokinetics of oxcarbazepine in humans.

In vitro antiepileptic effects of felbamate: possible involvement of excitatory amino acid receptors

In vitro antiepileptic effects of felbamate: possible involvement of excitatory amino acid receptors

Felbamate modulates the strychnine-insensitive glycine receptor

Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel anticonvulsant substance whose mechanism of action is not clearly understood. The present investigation examined its ability to modulate the strychnine-insensitive glycine receptor associated with the N-methyl-D-aspartate (NMDA) receptor. Felbamate decreased the magnitude of glycine (100 microM)-enhanced NMDA (100 microM)-induced intracellular calcium ([Ca2+]i) transients in mouse cerebellar granule cells which had been loaded with the Ca(2+)-sensitive fluorescent probe indo-1 acetoxymethyl ester (indo-1/AM). This effect of felbamate was concentration dependent, with a maximal effect observed at 300 microM (65 +/- 4% of control). In the Frings audiogenic seizure-susceptible mouse model of reflex epilepsy, the glycine agonist D-serine (150 nmol, i.c.v.) completely blocked the anticonvulsant activity of a maximally effective dose of felbamate (19 mg/kg, i.p.). This effect of D-serine could be reversed by increasing the administered dose of felbamate to 29 mg/kg. Furthermore, administration of D-serine (300 nmol, i.c.v.) to felbamate-treated Frings mice produced a parallel right shift in felbamate's anticonvulsant dose-response curve (ED50s: 9.4 mg/kg for felbamate vs. 17.7 mg/kg for felbamate + D-serine). The results obtained in this investigation suggest that the ability of felbamate to modulate the strychnine-insensitive glycine receptor may be physiologically and behaviorally relevant to its anticonvulsant mechanism of action.

Effects of Felbamate on Vigabatrin Pharmacokinetics

The effects of felbamate (F) on vigabatrin (V) pharmacokinetics were examined in 18 healthy volunteers. In this double-blind 2-way crossover study, subjects were administered V 1 gm q12h p.o. with F 1200mg or placebo (P) q12h p.o. for 8 days. Concentrations of the inactive R-(−) and active S-(+)-enantiomers of V were measured by GCMS, and AUC0-12 and Cmax values compared following F and P treatment.The pharmacokinetics of both enantiomers of V were similar during concurrent treatment with either F or P. Furthermore, coadministration of F and V was well tolerated by the volunteers.

Felbamate displays in vitro antiepileptic effects as a broad spectrum excitatory amino acid receptor antagonist

The in vitro antiepileptic activity of the novel anticonvulsant drug felbamate was tested in rat hippocampal slices on the CA1 epileptiform bursting induced by different chemical epileptogenic agents. The effects of felbamate were compared with those of the anticonvulsant drugs diphenylhydantoin and pentobarbitone and with the effects of excitatory amino acid antagonists acting at both N- methyl- D- aspartate (NMDA) and non-NMDA receptors. Like the non-NMDA receptor antagonist 6-cyano-7-nitro-quinoxaline-2, 3-dione (CNQX), felbamate at a minimum effective concentration of 1 mM induced a significant ( P < 0.01) reduction of the duration of the CA1 epileptiform bursting due to the K + channel blocker, 4-aminopyridine, and the excitatory amino acids, kainate and quisqualate. Like the NMDA receptor antagonist ketamine, felbamate (1.6 mM) significantly ( P < 0.01) decreased the duration of the CA1 epileptiform bursting caused by ‘Mg 2+-free’ solutions. Conversely, felbamate (1.6 mM), CNQX (100 μM) and ketamine (100 μM) failed to affect the epileptiform bursting induced by the GABA antagonist penicillin. Pentobarbitone (100 μM) significantly ( P < 0.01) decreased the duration of the CA1 epileptiform bursting caused by ‘Mg 2+-free’ solutions, 4-aminopyridine or penicillin, while diphenylhydantoin (up to concentrations of 100 μM) failed to have an effect. The results indicate that felbamate displays a unique profile of in vitro antiepileptic effects as a broad spectrum antagonist of excitatory amino acid transmission.

Felbamate: A new antiepileptic drug

The chemistry, pharmacology, pharmacokinetics, clinical use, adverse effects, drug interactions, and dosage of felbamate are discussed. Felbamate (2-phenyl-1,3-propanediol dicarbamate) is chemically unrelated to any of the other currently marketed antiepileptic drugs (AEDs). It appears that felbamate, like phenobarbital and valproic acid, decreases the frequency of seizures by decreasing seizure spread and increasing seizure threshold. Oral felbamate is at least 90% absorbed, and peak concentrations are reached in one to six hours. The half-life is a little less than one day. A therapeutic range of plasma concentrations has not been determined. Felbamate has been used effectively as monotherapy and adjunctive therapy in patients with partial seizures with or without secondary generalization and as adjunctive therapy in children with partial or generalized seizures associated with Lennox-Gastaut syndrome. Felbamate may also be safe and effective in patients with generalized, absence, atypical absence, juvenile myoclonic, infantile, and gelastic seizures. The most frequently reported adverse effects of felbamate include nausea, anorexia, vomiting, headache, fatigue, somnolence, insomnia, and increased serum aspartate aminotransferase levels. The frequency of adverse effects is greater in patients receiving other AEDs in addition to felbamate. Felbamate affects the pharmacokinetics of phenytoin, carbamazepine, valproic acid, and methsuximide; other AEDs also affect the pharmacokinetics of felbamate. The dosage of felbamate should begin at 400 mg orally three times daily and then increase by 600 mg/day every two weeks to up to 3600 mg/day. If the patient is receiving other AEDs concurrently, their dosage should be decreased as the dosage of felbamate is increased. If the goal is to switch to felbamate, the dosage should be increased weekly as the dosages of other AEDs are reduced. Felbamate offers a safe and effective alternative to other AEDs in the treatment of partial and secondarily generalized seizures; partial and generalized seizures associated with Lennox-Gastaut syndrome; and atypical absence seizures, gelastic seizures, and other difficult to control seizures.

Felbamate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy.

Felbamate is currently being developed as an antiepileptic agent. Although its mechanism of action has yet to be fully elucidated, felbamate appears to inhibit both the spread of seizures and increase seizure threshold in animal models. Data available in the clinical setting provide evidence that, at doses of up to 3600 mg/day as an adjunct to existing antiepileptic therapy or as monotherapy following substitution for other medications, the drug reduces the frequency of partial onset seizures in adult patients refractory to conventional antiepileptic treatments. Felbamate is also effective in the treatment of Lennox-Gastaut syndrome in children, a severe epilepsy which is usually refractory to antiepileptic agents. The effect of felbamate in the treatment of generalised tonic-clonic seizures in adults with partial onset seizures which are secondarily generalised is promising but requires clarification in large-scale trials. The most common adverse effects occurring during administration of felbamate are mild to moderate gastrointestinal (nausea, vomiting and anorexia) and central nervous system (headache, somnolence, diplopia, dizziness and insomnia) disturbances. Drug interactions with other antiepileptic agents may prove problematic in terms of adverse effects. Thus, at this stage of its development, the antiepileptic efficacy of felbamate in treatment-refractory patients with partial onset seizures and Lennox-Gastaut syndrome has been proven but efficacy in generalised tonic-clonic seizures requires further substantiation in large well controlled and well designed clinical trials. In addition, a more comprehensive base of comparative clinical trials data is necessary to further clarify issues of relative efficacy and tolerability compared with other antiepileptic agents. The clinical implications of the drug interactions associated with felbamate also require more detailed investigation. These data will be awaited with interest and when available will help to place felbamate in perspective in the management of epilepsy.

Effect of Felbamate on Plasma Levels of Carbamazepine and Its Metabolites

Felbamate (FBM) is a novel antiepileptic drug (AED) currently undergoing clinical evaluation in the United States. During a controlled clinical trial conducted at the National Institutes of Health Clinical Center, FBM was added to constant carbamazepine (CBZ) monotherapy. CBZ total concentrations were reduced during active FBM treatment (mean reduction 25%, range 10-42%, p less than 0.001). The effect was evident after the first week of treatment and reached a plateau in 2-4 weeks. To clarify the interaction mechanism, free and total concentrations of CBZ and its plasma metabolites were determined by high-performance liquid chromatography (HPLC) and ultrafiltration in four patients. In these patients, FBM treatment reduced CBZ concentrations and increased CBZ-epoxide (CBZ-E) concentrations (p less than 0.01). Free fractions of all compounds were unmodified. FBM appears to be capable of inducing CBZ metabolism. CBZ-FBM interaction may be clinically relevant.