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(Accepted August 7, 2001)
Carbamazepine (CBZ) has been extensively used in the treatment of epilepsy, as well as in the treatment of neuropathic pain and affective disorders. However, the mechanisms of action of this drug are not completely elucidated and are still a matter of debate. Since CBZ is not very effective in some epileptic patients and may cause several adverse effects, several antiepileptic drugs have been developed by structural variation of CBZ, such as oxcarbazepine (OXC), which is used in the treatment of epilepsy since 1990. (S)-(2)-10-acetoxy-10,11-dihydro-5H-dibenz [b,f ]azepine-5-carboxamide (BIA 2-093) and 10,11-dihydro-10-hydroxyimino -5H-dibenz[b,f ] azepine-5-carboxamide (BIA 2-024), which were recently developed by BIAL, are new putative antiepileptic drugs, with some improved properties. In this review, we will focus on the mechanisms of action of CBZ and its derivatives, OXC, BIA 2-093 and BIA 2-024. The available data indicate that the anticonvulsant efficacy of these AEDs is mainly due to the inhibition of sodium channel activity.
KEY WORDS: Antiepileptic drugs; mechanisms of action; carbamazepine; oxcarbazepine; BIA 2-093; BIA 2-024.
INTRODUCTION
Epilepsy is one of the most common neurological disorders, affecting about 50 million people worldwide. Phenobarbital, one of the first compounds utilized in the treatment of epilepsy, was introduced in 1912. Since then, several antiepileptic drugs (AEDs) have been developed, but only some of them have become established. It is estimated that the majority of epileptic patients are treated with only four drugs: phenobarbital, phenytoin, carbamazepine (CBZ) and valproic acid. CBZ (5H-dibenz[b,f ]azepine-5-carboxamide) was introduced in the early sixties, and has become the most frequently prescribed drug for the treatment of several forms of epilepsy. CBZ is also used in the treatment of neuropathic pain (1) and in psychiatric disorders (2).
CBZ is an iminodibenzyl derivative, structurally similar to the tricyclic antidepressants (Fig. 1). This drug is extensively metabolized in the liver, and only 1% of the administered dose is excreted in the unchanged form. The main oxidative pathway involves the formation of an active metabolite, carbamazepine-10,11-epoxide (3), which possesses anticonvulsant properties similar to those of CBZ.
Overall, the treatment with CBZ is effective and safe. However, approximately 30-40% of epileptic patients do not respond very well to the treatment (4) and CBZ may cause some adverse effects. For example, acute CBZ toxicity...