Disease relevance of felbamate

• Aplastic anemia in a patient receiving felbamate for complex partial seizures [1].
• Thirty-six cases of hepatic toxicity associated with felbamate therapy have been collected by the Food and Drug Administration. Five patients died [2].
• This review focuses on NMDA receptor antagonistic compounds, which are already in use for the treatment of epileptic seizures (i. e. MgSO4, felbamate) and compounds in clinical trials (i. e. remacemide, ADCI) [3].
• Protective effects of felbamate against hypoxia in the rat hippocampal slice [4].
• 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 [5].

Psychiatry related information on felbamate

• Interaction of felbamate with several other antiepileptic drugs against seizures induced by maximal electroshock in mice [6].
• Exploratory and spontaneous locomotor activities, after administration of some novel antiepileptic drugs (felbamate and lamotrigine alone or in combination), were evaluated in mice by means of the electronically monitored locomotor activity system (Digiscan analyzer) [7].

High impact information on felbamate

• Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate [8].
• The use of felbamate in the treatment of patients with intractable epilepsy [9].
• Following the occurrence of rare cases of aplastic anemia and of hepatic failure associated with the use of felbamate during early 1994, a "black-box" warning was added to the drug's package insert [10].
• Felbamate protects CA1 neurons from apoptosis in a gerbil model of global ischemia [5].
• Because felbamate inhibits the S-mephenytoin hydroxylase (CYP2C19) isozyme in vitro, it appears that phenobarbital hydroxylation is mediated in part by this isozyme [11].

Chemical compound and disease context of felbamate

• Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5% O2 for 1 hour [12].
• For example, felbamate may cause aplastic anaemia and fulminant liver failure, lamotrigine is prone to cause skin rash, and oxcarbazepine may cause symptomatic hyponatraemia [13].
• Because glycinergic mechanisms have been demonstrated to be involved with seizure disorders and neuroprotection, we investigated the binding interaction of felbamate with strychnine-insensitive glycine receptors and compared these findings with brain and plasma levels of felbamate after drug treatment [14].
• Liver disease is most likely with felbamate or valproic acid, but can occur with other anticonvulsants [15].
• Neuroprotective effect of felbamate after kainic acid-induced status epilepticus [16].

Biological context of felbamate

• Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive [17].
• No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment [17].
• Practice advisory: The use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society [18].
• The clinical implications of the drug interactions associated with felbamate also require more detailed investigation [19].
• Felbamate decreases synaptic transmission in the CA1 region of rat hippocampal slices [20].

Anatomical context of felbamate

• 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) [5].
• Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67% +/- 7% of neocortex in unmedicated rats to 32% +/- 8%, 51% +/- 12%, 38% +/- 19%, and 53% +/- 10% when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively [12].
• 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 [19].
• 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 [21].
• Blood-brain barrier penetration of felbamate [22].

Associations of felbamate with other chemical compounds

• Effects of felbamate on the pharmacokinetics of phenobarbital [11].
• 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 [17].
• Lamotrigine and felbamate seem to be effective in partial epilepsy and in Lennox-Gastaut syndrome [23].
• Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene [24].
• 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 [25].

Gene context of felbamate

• Felbamate induces CYP3A4, but inhibits CYP2C19 substrates [26].
• In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1 [24].
• 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 [27].
• Patients with FBM-associated aplastic anemia have deficient erythrocyte glutathione peroxidase, superoxide dismutase (SOD), and glutathione reductase activities compared with age-matched controls [28].
• The irreversible inhibition of GSTM1-1 may be important in understanding the toxicities associated with felbamate [29].

Analytical, diagnostic and therapeutic context of felbamate

• These data suggest that, in this animal model, felbamate given after a hypoxic-ischemic insult is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis, but that the window of opportunity for post hoc treatment is only 1 to 4 hours [12].
• 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 [30].
• Rectal administration of felbamate in a child with Lennox-Gastaut syndrome [31].
• The effects of felbamate on the pharmacokinetics of phenobarbital and one of its main metabolites, parahydroxyphenobarbital, were assessed in a parallel-group, placebo-controlled, double-blind study, in 24 healthy volunteers [11].
• Felbamate measured in serum by two methods: HPLC and capillary electrophoresis [32].

References