Oxcarbazepine

Schachter, Steven C.; Vázquez, Blanca; Fisher, Robert S.; Laxer, Kenneth D.; Montouris, Georgia; Combs-Cantrell, Deborah T.; Faught, Edward; Willmore, L. James; Morris, George L.; Ojemann, L. M.; Bennett, D.; Mesenbrink, Peter; Souza, José Diogo S.; Kramer, Lynn D.

doi:10.1212/wnl.52.4.732

Cited by 135 publications

(84 citation statements)

References 5 publications

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“…These results are confirmed by other monotherapy and adjunctive therapy studies in similar refractory patient populations (9,10,20) and provide evidence that 2400 mg/d OXC is a very effective dosage. The efficacy results from this study also indicate that OXC and CBZ appear to have different mechanisms of action, because 74% of patients in this study were already on CBZ and received additional benefit when OXC was added.…”

Section: Discussionsupporting

confidence: 76%

“…To investigate potential interactions with plasma MHD concentrations, ratios of mean steady-state (visits [6][7][8][9][10][11][12] to mean baseline (visits 1-3) plasma concentrations were calculated for each of the following concomitant AEDs: CBZ, valproic acid, phenobarbital, PHT, vigabatrin, clobazam, lamotrigine, clonazepam, primidone, diazepam, and gabapentin. Blood samples to determine trough plasma MHD concentrations were collected before the morning drug dose at visits 3, 6, 7, 9, 11, and 12. Approximately 7 mL of venous blood were collected and centrifuged at room temperature immediately after collection.…”

Section: Pharmacokinetic End Pointsmentioning

confidence: 99%

“…OXC has demonstrated efficacy as monotherapy in presurgical hospitalized patients with refractory partial seizures (9) and as adjunctive therapy in children (10). Therapeutic effects in monotherapy and adjunctive therapy were seen at dosages between 600 and 2400 mg/d.…”

mentioning

confidence: 99%

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Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

Barcs

Walker²,

Elger³

et al. 2000

Epilepsia

197

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Section: Discussionsupporting

confidence: 76%

Section: Pharmacokinetic End Pointsmentioning

confidence: 99%

See 1 more Smart Citation

Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

Barcs

Walker²,

Elger³

et al. 2000

Epilepsia

197

View full text Add to dashboard Cite

“…However, ethical issues on the use of placebo in such an experimental monotherapy situation remain. 25 Another variation of the newly diagnosed monotherapy design aimed at demonstrating a difference is to recruit a more generalized population with fewer seizures since diagnosis (and either no treatment or no chronic treatment) and randomize the patients into two groups: a good dose and a dose thought to be marginally effective (if effective at all). The analysis uses the time to n th -seizure as the primary outcome variable.…”

Section: Monotherapy Trialsmentioning

confidence: 99%

Clinical Development of Antiepileptic Drugs in Adults

Schmidt¹

2007

Neurotherapeutics

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Summary:Over the last two decades, ten so-called newer antiepileptic drugs (AEDs) have been approved around the world, the majority of which have found and maintained a place in the seizure-fighting armamentarium for the whole spectrum of epilepsies and epileptic syndromes; some of these drugs have features that are improved compared with the older drugs. Within that same time period, the process of clinical development of AEDs has also undergone changes and has become much more complex and costly. Efforts are underway to shift decision-making about the clinical viability of AED candidates to earlier development stages, using the concept of translational medicine. However, thus far all of the newer AEDs have undergone a standard development as an adjunct in the control of adult partial seizures; in some cases, development has been expanded to other seizure types and pediatric syndromes. Currently, the path to global approval for use in monotherapy is under review and is often debated with regulatory authorities. Clinical treatment guidelines consider randomized, blinded, well controlled studies as the premier level of evidence-based medicine; these studies originate mostly in confirmatory phases of the development program. However, with the rigid designs and criteria in regulatory driven trials, effectiveness in the clinical practice setting may not be sufficiently predicted by these studies, leading to frustrations from individual practitioners. Finally, additional safety issues regularly occur only after the postlaunch exposure to a broader population making necessary a continuing, and thorough, pharmacovigilance after the AED has come to market.

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“…Schacter et al (24) reported the first randomized, double-blind, placebo-controlled monotherapy study that involved 102 presurgical patients hospitalized at 10 United States epilepsy centers. Patients completed routine presurgical evaluation for refractory epilepsy after two to ten partial seizures and were off AEDs (except for lorazepam) for at least 48 h before randomization to monotherapy with OXC (rapidly titrated to 2,400 mg/day by day 2) or placebo.…”

Section: Adverse Events R Pht V Oxc In Adultsmentioning

confidence: 99%

Oxcarbazepine

Tecoma

1999

Epilepsia

122

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Summary:The success of carbamazepine (,CBZ) as a broadspectrum antiepileptic drug (AED) has led to its use as first-line therapy in children and adults for partial and generalized tonicclonic seizures. The limitations of CBZ include toxicity in sensitive individuals, autoinduction, which requires dose adjustment when therapy is initiated, and chronic hepatic induction, producing drug interactions when CBZ is used with AEDs and other drugs that undergo hepatic metabolism. One of two main products of CBZ microsomal metabolism, CBZ-I 0,ll -epoxide (formed by oxidation of the double bond between C-10 and C-1 l), appears to provide antiepileptic efficacy but contributes significantly to clinical toxicity. The most common adverse effects of CBZ are central nervous system (CNS) symptoms, followed by gastrointestinal, hepatic, endocrine disturbances, and teratogenic effects. Oxcarbazepine (OXC) was developed to provide a compound chemically similar enough to CBZ to mimic its efficacy and overall safety while improving its side- PHARMACOLOGY ChemistryOxcarbazepine (OXC, 10,11 -dihydro-10-0x0-carbamazepine) is a keto analogue of carbamazepine (CBZ). Like CBZ, it has a dibenzazepine nucleus bearing the 5-carboxamide substituent but is structurally different in the 10,11-position (Fig. 1). OXC is a neutral lipophilic compound with very low aqueous solubility. In humans, OXC is almost immediately converted to the main active metabolite, a 10-monohydroxy derivative, 10,ll ,dihydro-lO-hydroxy-5H-dibenzo( b,flazepine-5-carboxamide (MHD). Mechanism of actionBecause OXC is similar to CBZ in chemical structure and efficacy in animal models, the pharmacologic mechanisms of action may be similar. Inhibition of sustained, high-frequency, repetitive firing of voltagesensitive sodium action potentials has been investigated using intracellular recordings of spinal cord neurons in cell culture. Both MHD and OXC (EC,, = 2-5 x M, respectively) limited repetitive neuronal firing elicited by intracellularly applied depolarizing currents at stable membrane potentials (Em -49 to -55 mV) (1-3). These effects were seen at concentrations much lower than plasma concentrations in patients treated with OXC. Furthermore, the limitation of repetitive firing was found to be frequency-dependent. The V,,, of the neuronal action potentials decreased with successive firing rates, and the percent of stimuli that elicited action potentials decreased significantly as the frequency was increased from 1 to 100 Hz in the presence of M OXC or MHD. These results suggest that blockade of voltagesensitive sodium channels could contribute to the antiepileptic efficacy of OXC and MHD.Blockade of penicillin-induced bursts in hippocampal slices has also been investigated as a measure of antiepileptic efficacy through an effect on potassium channels. MHD was shown to reduce the discharge frequency, and the effect was antagonized by co-application of 4-aminopyridine, a potassium channel blocker ( 1).Thus, MHD appears to have an additional effect on the potassium-dependen...

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Oxcarbazepine

Abstract: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.

Cited by 135 publications

References 5 publications

Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

Clinical Development of Antiepileptic Drugs in Adults

Oxcarbazepine

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