Epilepsia
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This article surveys the pharmacokinetic parameters for the new antiepileptic drugs (AEDs): felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin. Compared to the pharmacokinetics of standard AEDs, these new AEDs have progressed in terms of (a) longer half-lives, permitting once- or twice-daily dosing, (b) greatly reduced potential for drug interactions, thus increasing ease of treatment, and (c) general lack of hepatic enzyme induction, which facilitates polytherapy as well as other aspects of treatment.
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In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). ⋯ The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.
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Established antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium channels, gamma-aminobutyric acid type A (GABAA) receptors, or calcium channels. Benzodiazepines and barbiturates enhance GABAA receptor-mediated inhibition. ⋯ The mechanism of action of oxcarbazepine (OCBZ) is not known; however, its similarity in structure and clinical efficacy to CBZ suggests that its mechanism of action may involve inhibition of sustained high-frequency repetitive firing of voltage-dependent sodium action potentials. Vigabatrin (VGB) irreversibly inhibits GABA transaminase, the enzyme that degrades GABA, thereby producing greater available pools of presynaptic GABA for release in central synapses. Increased activity of GABA at postsynaptic receptors may underline the clinical efficacy of VGB.
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Review of randomized controlled trials (RCTs) shows that valproate (VPA) is effective against partial seizures with or without becoming secondarily generalized. A number of RCTs show little difference in the efficacy of VPA and carbamazepine in this patient group, particularly where patients are randomized at the time of diagnosis. The length of time that it has taken to arrive at these conclusions emphasizes the importance of large active-controlled RCTs at an early stage in drug development in informing clinical practice.
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Review Comparative Study
A comment on the efficacy of valproate in the treatment of partial seizures.
Discrepancies in the findings of studies sponsored by the Department of Veterans Affairs (VA) in the United States and the Medical Research Council (MRC) in the United Kingdom concerning the efficacy of valproate (VPA) in controlling simple or complex partial seizures, particularly those without secondarily generalized seizures, were reviewed. It was noted that the two studies differed with respect to their subjects' pretreatment seizure frequency. The frequency of complex partial seizures before treatment was obviously greater in the VA study, where carbamazepine (CBZ) provided better seizure control than VPA. Based on other comparative and non-comparative studies as well as the author's over 20 years of experience in the use of VPA in a tertiary epilepsy clinic, it is suggested that although VPA may be effective in controlling both the secondarily generalized seizures of symptomatic localization-related epilepsies and the generalized tonic-clonic seizures of idiopathic and, if not always, symptomatic generalized epilepsies, the efficacy of VPA in controlling simple or complex partial seizures is likely limited to patients with infrequent seizures.