The Experts below are selected from a list of 639 Experts worldwide ranked by ideXlab platform
Angela De Sarro - One of the best experts on this subject based on the ideXlab platform.
-
gabapentin potentiates the antiseizure activity of certain anticonvulsants in dba 2 mice
European Journal of Pharmacology, 1998Co-Authors: Giovambattista De Sarro, Pietro Gareri, C Spagnolo, Luca Gallelli, Angela De SarroAbstract:Gabapentin (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in Dilute Brown Agouti DBA2J (DBA/2) mice in a dose-dependent manner. Gabapentin at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, Felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The potentiation induced by gabapentin was greatest for diazepam, phenobarbital and valproate, less for Felbamate and phenytoin and least for carbamazepine and lamotrigine. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment of the above drugs + gabapentin was more favourable than that of the same drugs + saline. Since gabapentin did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that gabapentin can modify the clearance from the brain of the anticonvulsant drugs studied can not be excluded. In addition, gabapentin did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, gabapentin showed an additive effect when administered in combination with certain classical anticonvulsants, most notably diazepam, phenobarbital, Felbamate, phenytoin and valproate.
-
anticonvulsant activity of 5 7dcka nbqx and Felbamate against some chemoconvulsants in dba 2 mice
Pharmacology Biochemistry and Behavior, 1996Co-Authors: Giovambattista De Sarro, Ennio Ongini, Rosalia Bertorelli, Umberto Aguglia, Angela De SarroAbstract:Abstract The anticonvulsant effects of Felbamate (10–300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5–7dichlorokynurenic acid (5–7DCKA; 0.6–30 nmol/mouse, intracerebroventricularly, ICV), and 2,3-dihydroxy-6 nitro-7-sulfamoylbenzo(F)quinoxoline (NBQX; 1.1–33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N -methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, Felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED 50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1–40 mg/kg IP) was uneffective, while 5,7DCKA (5–90 nmol/mouse, ICV) protected mice against tonus. Moreover, Felbamate prevented seizures induced by blocking voltage-dependent K + channels using α-dendrotoxin, with ED 50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by α-dendrotoxin. The present data indicate that Felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.
-
excitatory amino acid neurotransmission through both nmda and non nmda receptors is involved in the anticonvulsant activity of Felbamate in dba 2 mice
European Journal of Pharmacology, 1994Co-Authors: G B De Sarro, Rosalia Bertorelli, Ennio Ongini, Umberto Aguglia, Angela De SarroAbstract:The anticonvulsant activity of Felbamate against sound-induced seizures was studied in the DBA/2 mouse model. Felbamate (10-300 mg/kg, i.p.) produced dose-dependent effects with ED50 values for the suppression of tonic, clonic and wild running phases of 23.1, 48.8 and 114.6 mg/kg, respectively. Felbamate also protected DBA/2 mice from N-methyl-D-aspartate (NMDA)-induced seizures with ED50 values of 12.1 and 29 mg/kg for tonus and clonus, respectively. Pretreatment with glycine, an agonist to the glycine/NMDA receptors, shifted the dose-response effect of Felbamate to the right (ED50 = 56.8 against tonus and 94.8 mg/kg versus clonus). Similarly, D-serine, an agonist at the glycine site, shifted the ED50 of Felbamate against the tonic component of audiogenic seizures from 23.1 to 78.1, and that against clonus from 48.8 to 90.3 mg/kg. Felbamate was also potent to prevent seizures induced by administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an AMPA/kainate receptor agonist (ED50 = 11.8 and 20.9 mg/kg, against tonus and clonus, respectively). The data indicate that Felbamate is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our findings suggest that the anticonvulsant properties of Felbamate depend upon its interaction with neurotransmission mediated by both the glycine/NMDA and the AMPA/kainate receptor complex.
Duane R Sofia - One of the best experts on this subject based on the ideXlab platform.
-
Felbamate protects ca1 neurons from apoptosis in a gerbil model of global ischemia
Stroke, 1996Co-Authors: Claude G. Wasterlain, Lisa M. Adams, Joseph Wichmann, Duane R SofiaAbstract:Background and Purpose Felbamate, a novel anticonvulsant that binds to the glycine site of the N -methyl-d-aspartate receptor, has been shown to have neuroprotective properties in vitro and in vivo. In a rat pup model of hypoxia-ischemia, Felbamate selectively reduced delayed death in hippocampal granule cells. The present study explores its neuroprotective potential in a gerbil model of global ischemia, in which good evidence exists that ischemia triggers apoptosis of CA1. Methods Gerbils were subjected to bilateral carotid occlusion for 5 minutes and then treated with Felbamate (100 or 200 mg/kg IV) or vehicle. They were killed 3 days later, and the numbers of live and dead neurons in the CA1 sector of the hippocampus were counted at stereotaxically defined levels. Results Felbamate (200 mg/kg IV) administered after the release of carotid clamping did not change brain temperature but reduced neuronal death in CA1 from 332±60 cells per section of dorsal hippocampus in unmedicated gerbils to 62±12 cells in Felbamate-treated animals ( P <.001). A lower dose of Felbamate (100 mg/kg post hoc) showed only a nonsignificant reduction of neuronal death. In the 200-mg/kg group, Felbamate serum concentrations peaked at 162 μg/mL and were above 100 μg/mL for at least 3 hours, and brain levels reached 150 μg/mL at 1 hour. In the 100-mg/kg group, blood serum levels were well below 100 μg/mL. Conclusions These results suggest that Felbamate given post hoc is remarkably effective in preventing delayed apoptosis secondary to global ischemia but that effective neuroprotection requires doses higher than those used for anticonvulsant treatment.
-
Felbamate modulates the strychnine insensitive glycine receptor
Epilepsy Research, 1995Co-Authors: Steve H White, Duane R Sofia, Wendy L Harmsworth, Harold H WolfAbstract: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.
-
blood brain barrier penetration of Felbamate
Epilepsia, 1992Co-Authors: Eain M Cornford, Deborah Young, James W Paxton, Duane R SofiaAbstract: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.
Michael A Rogawski - One of the best experts on this subject based on the ideXlab platform.
-
Felbamate block of recombinant n methyl d aspartate receptors selectivity for the nr2b subunit
Epilepsy Research, 2000Co-Authors: Patrick T Harty, Michael A RogawskiAbstract:The anticonvulsant Felbamate blocks N-methyl-D-asparate (NMDA) receptors but fails to exhibit the neurobehavioral toxicity characteristic of other NMDA receptor antagonists. To investigate the possibility that Felbamate's favorable toxicity profile could be related to NMDA receptor subtype selectivity, we examined the specificity of Felbamate block of recombinant NMDA receptors composed of the NR1a subunit and various NR2 subunits. Felbamate produced a rapid, concentration-dependent block of currents evoked by 50 microM NMDA and 10 microM glycine in human embryonic kidney 293 cells expressing the rat NR1a subunit, and either the NR2A, NR2B or NR2C subunits; the IC50 values for block were 2.6, 0.52 and 2.4 mM, respectively (holding potential, - 60 mV). The Hill coefficient values were < 1 and, in kinetic analyses, onset and recovery from block were well fit by double exponential functions, indicating binding to more than one blocking site on the NMDA receptor channel complex. The higher affinity of Felbamate block of NMDA receptors containing the NR2B subunit could be accounted for by more rapid association and slower dissociation from these sites. We conclude that Felbamate exhibits modest selectivity for NMDA receptors composed of NR1a/NR2B subunits. This selectivity could, in part, account for the more favorable clinical profile of Felbamate in comparison with NMDA receptor antagonists that do not show subunit selectivity.
-
barbiturate like actions of the propanediol dicarbamates Felbamate and meprobamate
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Jong M Rho, Sean D Donevan, Michael A RogawskiAbstract:Felbamate and meprobamate are structurally related propanediol dicarbamates that possess distinct pharmacological profiles. Felbamate is a minimally sedative, broad-spectrum anticonvulsant, whereas meprobamate is a strong sedative-anxiolytic agent. Previously, we reported that Felbamate potentiates γ-aminobutyric acidA(GABAA) receptor Cl− currents and inhibits N-methyl-d-aspartate (NMDA) receptor currents. Here we further characterized the interaction of the two dicarbamates with GABAA receptors to determine the basis for their pharmacological differences. In whole-cell voltage-clamp recordings from cultured rat hippocampal neurons, meprobamate enhanced GABA-evoked responses in a concentration-dependent manner and, at high concentrations (>1 mM), exhibited a separate channel-blocking effect that limited the magnitude of GABAA receptor potentiation. At equivalent concentrations, meprobamate produced substantially greater potentiation than did Felbamate. Furthermore, meprobamate (but not Felbamate), in the absence of GABA, directly activated Cl− currents that could be attenuated by the GABAA receptor antagonists bicuculline and picrotoxin. The mean deactivation time constant of whole-cell currents evoked by 10 mM meprobamate (110 ms) or 1 and 3 μM GABA (180 ms) were faster than the deactivation time constant of 10 mM meprobamate (490 ms) or 3 mM Felbamate (470 ms) in the presence of GABA. Meprobamate and Felbamate prolonged the mean burst duration of GABA-activated unitary currents in excised outside-out membrane patches. In addition, at high (supratherapeutic) concentrations, meprobamate blocked NMDA-activated currents. We conclude that Felbamate and meprobamate have barbiturate-like modulatory actions on GABAA receptors, but meprobamate has greater activity and, unlike Felbamate, is able to directly activate the receptor.
-
Felbamate block of the n methyl d aspartate receptor
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: Swaminathan Subramaniam, Jong M Rho, Sean D Donevan, Laroy Penix, R P Fielding, Michael A RogawskiAbstract:The anticonvulsant Felbamate may act as an N-methyl-D-aspartate (NMDA) receptor antagonist, but the mechanism of block has not been fully characterized. We sought to identify the sites at which Felbamate exerts its NMDA receptor blocking action using radioligand binding to rat forebrain membranes and whole-cell voltage clamp and single-channel recordings from cultured rat hippocampal neurons. Equilibrium binding isotherms for [3H]dizocilpine, a channel blocking ligand, were obtained in the presence of saturating glutamate and glycine. At a concentration of 1 mM, Felbamate competitively inhibited specific [3H]dizocilpine binding, indicating that Felbamate interacts with the channel blocking site. At a higher concentration (3 mM), Felbamate also reduced the maximal saturation binding, demonstrating an additional allosteric action. The dissociation constant (Kb), estimated from fits to the binding isotherms, was 0.7-1.1 mM. It has been proposed that Felbamate block of NMDA receptors occurs via competitive glycine site antagonism. However, the slowing of [3H]dizocilpine dissociation by Felbamate, unlike the slowing produced by 7-chlorokynurenic acid, was not reversed by increasing the glycine concentration. In addition, Felbamate did not reduce specific binding of [3H]5,7-dichlorokynurenic acid, a glycine site ligand. In whole-cell voltage clamp recordings of NMDA receptor currents, its blocking time constant (69 +/- 0.4 msec) was substantially faster than the dissociation time constant of glycine (390 +/- 23 msec), whereas the time constant for 5,7-dichlorokynurenic acid (390 +/- 20 msec) was similar. These observations indicate that Felbamate block of NMDA receptors does not occur by an action at the glycine site.(ABSTRACT TRUNCATED AT 250 WORDS)
-
mechanism of action of the anticonvulsant Felbamate opposing effects on n methyl d aspartate and γ aminobutyric acida receptors
Annals of Neurology, 1994Co-Authors: Jong M Rho, Sean D Donevan, Michael A RogawskiAbstract:Felbamate is a promising new antiepileptic drug whose mechanism of action is unknown. In whole-cell voltage clamp recordings from cultured rat hippocampal neurons, clinically relevant concentrations of Felbamate (0.1-3 mM) inhibited N-methyl-D-aspartate (NMDA) responses and potentiated gamma-aminobutyric acid (GABA) responses. Single-channel recordings indicated that the effect on NMDA responses occurred via a channel blocking mechanism. Felbamate is the first anticonvulsant drug with dual actions on excitatory (NMDA) and inhibitory (GABA) brain mechanisms. This unique combination of effects could account for Felbamate's broad spectrum of anticonvulsant activity in animal seizure models and its distinctive clinical efficacy and safety profile.
Jinsong Geng - One of the best experts on this subject based on the ideXlab platform.
-
Felbamate add on therapy for drug resistant focal epilepsy
Cochrane Database of Systematic Reviews, 2019Co-Authors: Li Li Shi, Rebecca Bresnahan, Kirsty J Martinmcgill, Jiancheng Dong, Jinsong GengAbstract:Background This is an updated version of the Cochrane Review previously published in 2017.Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. Objectives To evaluate the efficacy and tolerability of Felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. Search methods For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of Felbamate and experts in the field for information about any unpublished or ongoing studies. Selection criteria We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Data collection and analysis Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. Main results We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on Felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between Felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on Felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for Felbamate-randomised participants. Notably, the treatment withdrawal rates for Felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that Felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of Felbamate-treated participants versus 3% to 15% of placebo-treated participants.We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of Felbamate could likely be significantly different from that reported in this current review update. Authors' conclusions In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of Felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.
-
Felbamate as an add on therapy for refractory partial epilepsy
Cochrane Database of Systematic Reviews, 2017Co-Authors: Li Li Shi, Jiancheng Dong, Jinsong GengAbstract:Background This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. Objectives To evaluate the efficacy and tolerability of Felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. Search methods For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of Felbamate and experts in the field for information about any unpublished or ongoing studies. Selection criteria Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. Data collection and analysis Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. Main results We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the Felbamate period than the placebo period, particularly headache, nausea and dizziness. Authors' conclusions In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of Felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.
-
Felbamate as an add on therapy for refractory epilepsy
Cochrane Database of Systematic Reviews, 2014Co-Authors: Li Li Shi, Jiancheng Dong, Jinsong GengAbstract:BACKGROUND This review is an update of a previously published review in The Cochrane Database of Systematic Reviews (Issue 1, 2011) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and its effects as an add-on therapy to standard drugs are assessed in this review. OBJECTIVES To evaluate the efficacy and tolerability of Felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH METHODS We searched the Cochrane Epilepsy Group Specialized Register (24 July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), and PubMed (24 July 2013). This search was run for the original review on 20 May 2010. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of Felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA Randomized placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or crossover design. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS Three randomised controlled trials with a total of 153 participants were included. The first was a parallel design, the second had a two-period crossover design, and the third had a three-period crossover design. One study was at unclear risk of bias for random sequence generation and allocation concealment. And in the same study, there was no description of how to blind outcome assessment, performance blinding was for participants, might not be for doctors. Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. None of the three studies reported 50% or greater reduction in seizure frequency. Only one study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. Adverse effects rates were higher during the Felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS In view of the methodological deficiencies, limited number of individual studies and differences in outcome measure, we have found no reliable evidence to support the use of Felbamate as an add-on therapy in patients with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.Since the last version of this review no new studies have been found.
Giovambattista De Sarro - One of the best experts on this subject based on the ideXlab platform.
-
influence of carbenoxolone on the anticonvulsant efficacy of conventional antiepileptic drugs against audiogenic seizures in dba 2 mice
European Journal of Pharmacology, 2004Co-Authors: Pietro Gareri, Guido Ferreri, Eugenio Donato Di Paola, Santo Gratteri, Natale Belluardo, Daniele Filippo Condorelli, Giovambattista De SarroAbstract:Abstract Carbenoxolone, the succinyl ester of glycyrrhetinic acid, is an inhibitor of 11β-hydroxy steroid dehydrogenase and gap junctional intercellular communication. It is currently used in clinical treatment of ulcer diseases. Systemic administration of carbenoxolone (1–40 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. Glycyrrhizin, an analogue of carbenoxolone inactive at the gap-junction level, was unable to affect audiogenic seizures at doses up to 30 mg/kg. In combination with conventional antiepileptic drugs, carbenoxolone, 0.5 mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, Felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. This effect was not observed after the combination of glycyrrhizin (10 mg/kg, i.p.) with some conventional antiepileptic drugs. The degree of potentiation induced by carbenoxolone was greater for diazepam, Felbamate, gabapentin, phenobarbital and valproate, less for lamotrigine, phenytoin and carbamazepine. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with carbenoxolone was more favourable than the combination with glycyrrhizin or saline. Since carbenoxolone did not significantly influence the total and free plasma levels of diazepam, Felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital, valproate and carbamazepine, pharmacokinetic interactions are not likely. However, the possibility that carbenoxolone can modify the brain clearance of the anticonvulsant drugs studied may not be excluded. In addition, carbenoxolone did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, carbenoxolone showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably diazepam, Felbamate, gabapentin, phenobarbital, and valproate, implicating a possible therapeutic relevance of such drug combinations.
-
gabapentin potentiates the antiseizure activity of certain anticonvulsants in dba 2 mice
European Journal of Pharmacology, 1998Co-Authors: Giovambattista De Sarro, Pietro Gareri, C Spagnolo, Luca Gallelli, Angela De SarroAbstract:Gabapentin (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in Dilute Brown Agouti DBA2J (DBA/2) mice in a dose-dependent manner. Gabapentin at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, Felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The potentiation induced by gabapentin was greatest for diazepam, phenobarbital and valproate, less for Felbamate and phenytoin and least for carbamazepine and lamotrigine. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment of the above drugs + gabapentin was more favourable than that of the same drugs + saline. Since gabapentin did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that gabapentin can modify the clearance from the brain of the anticonvulsant drugs studied can not be excluded. In addition, gabapentin did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, gabapentin showed an additive effect when administered in combination with certain classical anticonvulsants, most notably diazepam, phenobarbital, Felbamate, phenytoin and valproate.
-
anticonvulsant activity of 5 7dcka nbqx and Felbamate against some chemoconvulsants in dba 2 mice
Pharmacology Biochemistry and Behavior, 1996Co-Authors: Giovambattista De Sarro, Ennio Ongini, Rosalia Bertorelli, Umberto Aguglia, Angela De SarroAbstract:Abstract The anticonvulsant effects of Felbamate (10–300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5–7dichlorokynurenic acid (5–7DCKA; 0.6–30 nmol/mouse, intracerebroventricularly, ICV), and 2,3-dihydroxy-6 nitro-7-sulfamoylbenzo(F)quinoxoline (NBQX; 1.1–33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N -methyl-D-aspartate (NMDA) or α-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, Felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED 50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1–40 mg/kg IP) was uneffective, while 5,7DCKA (5–90 nmol/mouse, ICV) protected mice against tonus. Moreover, Felbamate prevented seizures induced by blocking voltage-dependent K + channels using α-dendrotoxin, with ED 50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by α-dendrotoxin. The present data indicate that Felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.
