Felbamate anticonvulsant

Anticonvulsants (barbiturates, including phenobar-bital and primidone carbamazepine felbamate phenytoin topiramate vigabatrin)... 

Scheme 15.1 Postulated bioactivation pathways of the anticonvulsant agent felbamate rational chemical approach to circumvent bioactivation by fluorofelbamate.

Felbamate, a new anticonvulsant, has beneficial effects in partial and secondarily generalized seizures.lt can reduce symptoms in Lennox-Gastaut syndrome. However an association with aplastic anemia reduces its usefulness and Lennox-Gastaut syndrome is considered to be its only indication. 

Excitatory neurotransmitters also may be involved in the appearance of epilepsy, since the bursting activity typically seen during epileptic discharges may be due in part to the action of glutamate acting on A-methyl-o-aspartate (NMDA) receptor channels to produce depolarization. It is likely that a major part of the anticonvulsant activity of felbamate involves blockade of the NMDA receptor. Table 32.2 summarizes the most likely mechanism of action associated with available anticonvulsant drugs. 

While its mechanism of action has not been clearly established, felbamate shows some activity as an inhibitor of voltage-dependent sodium channels in a manner similar to that of phenytoin and carbamazepine. Felbamate also interacts at the strychnine-insensitive glycine recognition site on the NMDA receptor-ionophore complex. Whether this effect is important to its anticonvulsant activity is not clear. 

The newer anticonvulsants have not been studied as intensively as the older drugs, but felbamate, oxcarbaze-pine, and topiramate have enzyme-inducing activity and reduce plasma steroid concentrations (331). 

Changes in body weight associated with anticonvulsants have been reviewed (116), including the effects of the antiepileptic drugs that have been most commonly associated with this adverse effect (valproic acid, carbamazepine, vigabatrin, and gabapentin) (117). Unlike most anticonvulsants, topiramate, felbamate, and zonisamide can cause weight loss. 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

Nausea, vomiting, diarrhea, and changes in appetite can occur with all anticonvulsants, although they are usually transient and rarely require withdrawal. Felbamate and to a lesser extent valproate are the anticonvulsants that most often cause gastrointestinal adverse effects. 

Of 34 cases of aplastic anemia (mean age 41 years, mean time of felbamate exposure 154 days), 20 occurred in combination with other compounds implicated as a possible cause of aplastic anemia and 5 occurred concurrently with viral infections (7). Although 5 patients were taking felbamate monotherapy, 13 of the 34 suffered from autoimmune disease, and 1 was receiving cytostatic therapy. Past allergic or toxic reactions to other anticonvulsants were reported by 65% of the patients and blood dyscrasias by 45%, while 32% had serological evidence of a previous immune disorder. Eight of nine patients tested had experienced at least one episode of aplastic anemia associated with HLA antigens. 

Felbamate. Felbamate is an adjuvant anticonvulsant, containing the warning that its use is associated with a marked increase in the incidence of aplastic anemia and that patients being started on the drug should have liver function tests performed before therapy is initiated. Animal studies have revealed a statistically significant increase in hepatic cell adenomas in high dose studies (18). It is postulated that this cancer was induced by toxic by-products urethane and methyl carbamate. Felbamate is not recommended as first-line therapy and is indicated for those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia or liver failure is deemed acceptable in light of the benefits provided by its use. 

A review of the second-generation anticonvulsants reveals that screening or serendipity led to the development of felbamate (10), 1am-otrigine (11), zonisamide (13), topiramate (15), and levetiracetam (16) on the other hand, clobazam (4d) and oxcarbazepine (12) were developed by structural variation of known agents (78). Only three, vigabatrin (8), gabapentin (9), and tiagabine (14), were developed by mechanism-based rational development (78). 

Table IV-1 -3 summarizes the mechanisms, indications for use, and potential toxic effects of some i newer anticonvulsants. Those listed are felbamate, gabapentin, lamotrigine, tiagabine, topiramate, and j...

Newer anticonvulsants listed are felbamate, gabapentin, and lamotrigine. 

Examples of activated double bond electrophiles include a, 3-unsaturated carbonyl compounds, quinones, quinoneimines, quinonemethides and diiminoquinones as shown in Fig. 10.32B. These electrophilic intermediates are highly polarized and can react with nucleophiles in a 1,4-Michael-type addition at the more electrophilic or 3-oarbon of the activated double bond intermediate to the addition product (Fig. 10.32A). Specific examples of activated double bond electrophiles that have been proposed for the anticancer drug leflunamide, the food antioxidant butylated hydroxytoluene, acetaminophen, the antiandrogen flutamide, the anticonvulsant felbamate and the cytotoxic cyclophosphamide as shown in Fig. 10.32C. The bioinaotivation pathways for these electrophilic intermediate can involve either direct addition, with or without transferases, depending upon the degree of polarization and reactivity of the electrophilic intermediate (hard vs soft electrophiles). 

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