Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rufinamide [E 2080, CGP 33101, RUF 331, Inovelon, Xilep] is the lead compound in a series of five-substituted phenylalkyl-3- carbamoyl-4H-1,2,4-triazoles with anticonvulsant activity that was discovered by Novartis AG. Although the precise mechanism of action for rufinamide is unknown, it is known that it limits the firing of sodium-dependent action potentials in neurons, hinting at a membrane-stabilising effect. Rufinamide is under regulatory review in Europe for epilepsy, and phase III trials in the same indication are underway with Eisai in the US. In February 2004, Eisai Co. Ltd announced that it had signed an in-licensing agreement with Novartis Pharma AG for the exclusive worldwide rights to manufacture, develop and market rufinamide for the treatment of epilepsy. Eisai submitted an MAA for rufinamide (Inovelon) as an adjunct therapy of seizures associated with Lennox-Gastaut Syndrome to the European Medicines Agency through the centralised procedure in March 2005. The drug also received orphan drug designation from the European commission in October 2004 for this indication. Eisai also plans to file for regulatory approval in the US. Rufinamide has demonstrated statistically significant efficacy as an adjunctive therapy in adult patients with epilepsy and in patients with seizures associated with Lennox-Gastaut syndrome. Novartis stated in June 2001, prior to the licensing agreement with Eisai, that it had stopped development of rufinamide in the US, Japan and Europe for neuropathic pain (at phase II) and epilepsy (at phase III).
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PMID:Rufinamide: CGP 33101, E 2080, RUF 331, Xilep. 1599 87

Rufinamide, a triazole derivative, reduces the recovery capacity of neuronal sodium channels after inactivation, limiting neuronal sodium-dependent action potential firing and mediating anticonvulsant effects. In children, adolescents and adults, adjunctive oral rufinamide was more effective than placebo in treating seizures associated with treatment-resistant Lennox-Gastaut syndrome in a well designed 16-week trial. Rufinamide recipients experienced significantly greater reductions from baseline than placebo recipients in the median frequency of total seizures and tonic-atonic seizures per 28 days and demonstrated improvements in seizure severity. Furthermore, these beneficial effects of rufinamide on seizure frequency were maintained throughout a subsequent 3-year, open-label extension study. Relative to placebo, adjunctive rufinamide significantly reduced the frequency of partial seizures per 28 days in adult patients with inadequately controlled partial seizures in two well designed trials of approximate, equals3 months duration, with a higher proportion of rufinamide recipients achieving a reduction of >or=50% in partial seizure frequency per 28 days. Rufinamide was generally well tolerated in patients with Lennox-Gastaut syndrome and in those with partial seizures, with adverse events being mostly mild or moderate in severity.
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PMID:Rufinamide. 1695 53

Rufinamide is a structurally novel compound with anticonvulsant activity that is undergoing evaluation through the European Medicines Agency and the American Food and Drug Administration. Its mechanism of action is thought to be inhibition of sodium-dependent action potentials in neurons, with possible membrane-stabilising effects. Absorption of the drug is significantly enhanced in the fed state. The drug is extensively metabolised by non-CYP450 systems with a half-life of 8-12 h. Most common adverse effects noted are somnolence, fatigue and tremor. Efficacy against partial seizures in adults and adolescents has been demonstrated in three randomised, placebo-controlled trials. Efficacy against seizures of Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single randomised, placebo-controlled trial. Efficacy against partial onset seizures in children has been suggested in an open-label trial. Should rufinamide become commercially available, reserving the drug as a second- or third-line agent should be considered.
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PMID:Rufinamide: Pharmacology, clinical trials, and role in clinical practice. 1707 44

Rufinamide is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs. Rufinamide was profiled for anticonvulsant activity at the National Institutes of Health and showed broad-spectrum anticonvulsant properties at nontoxic doses in animal models. The principal mechanism of action of rufinamide is considered to be the modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide provides an efficacious and well-tolerated treatment option for use as adjunctive therapy in patients with partial seizures and with Lennox-Gastaut syndrome (LGS). In LGS, rufinamide is effective in controlling multiple seizure types and in reducing the severity of the seizures. The most commonly observed (> or =10%) adverse experiences seen in association with rufinamide are headache, dizziness, fatigue, somnolence and nausea. Rufinamide is generally well tolerated, and its safety profile is well-established.
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PMID:Rufinamide. 1719 32

Rufinamide (1-[2,6-difluorobenzyl]-1H-1,2,3-triazole-4-carboxamide) is a new anti-epileptic drug with a novel triazole derivative structure. The suspected mechanism of action is limitation of sodium-dependent action potentials, thought to result in a membrane stabilizing effect. Rufinamide is extensively metabolized in the liver by non-CYP450 enzymes with an elimination half-life of 8 - 12 h. Three randomized, placebo-controlled trials have shown that rufinamide is effective against partial seizures in adults. Efficacy in the Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single, randomized, placebo-controlled trial. It has recently been approved for treatment of Lennox-Gastaut syndrome in Europe. In the US it is under regulatory review. Most common adverse effects are somnolence, fatigue, dizziness, dipolopia, nausea and ataxia. Rufinamide has shown promise as adjunctive treatment for Lennox-Gastaut syndrome and may have some role in localization related epilepsies as well.
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PMID:Rufinamide: a new anti-epileptic medication. 1769 94

Rufinamide is a new antiepileptic drug that is effective in acute animal seizure models and also in the kindling model of epilepsy with a high protective index. Its mechanism of action is largely unknown; studies suggest an effect at voltage-gated sodium channels, but whether this is its main mode of action remains to be determined. Rufinamide can be administered twice daily and has minimal drug interactions (it does, however, interact with the contraceptive pill). Food markedly increases absorption, which may complicate clinical use. Trials indicate that rufinamide is effective as adjunctive therapy in partial epilepsy and the Lennox-Gastaut syndrome with minimal adverse effects including headache, dizziness and fatigue. In addition, rufinamide has a favorable cognitive side-effect profile. However, it remains uncertain whether rufinamide offers significant advantages over other current antiepileptic drugs, and the results of further clinical trials are awaited.
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PMID:Rufinamide. 1772 46

Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V(d)/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of -13.7% in female children comedicated with vigabatrin to a maximum of -46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related.
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PMID:Rufinamide: clinical pharmacokinetics and concentration-response relationships in patients with epilepsy. 1850 64

There is still a need for new antiepileptic drugs (AEDs) as the clinical efficacy, tolerability, toxicity or pharmacokinetic properties of existing AEDs may not be satisfactory. One new AED has recently been approved (rufinamide in 2007) and six others are in late-stage development (phase III and onwards) [brivaracetam, carisbamate, eslicarbazepine, lacosamide, retigabine and stiripentol]. The purpose of this review is to provide updated data on proposed mechanisms of action, efficacy and tolerability on these new AEDs, and to discuss the rationale for their development and possible advantages compared with existing treatment, based on recent publications and MEDLINE searches.Rufinamide, brivaracetam and stiripentol have been given the status of orphan drugs. Rufinamide was approved in Europe in 2007 for the use in Lennox-Gastaut syndrome. Brivaracetam has gained orphan status for development in progressive and symptomatic myoclonic seizures in Europe and the US, respectively. Stiripentol has gained orphan status in children with Dravet's syndrome and pharmaco-resistant epilepsy. All of these drugs demonstrate efficacy as adjunctive therapy in partial seizures. Three of the drugs are derivatives of existing AEDs: brivaracetam is a derivative of levetiracetam with improved affinity for the target molecule; carisbamate is a derivative of felbamate with improved tolerability; and eslicarbazepine is a derivative of carbamazepine with less interaction potential and no auto-induction. Lacosamide, retigabine, rufinamide and stiripentol are new compounds, unrelated to other AEDs.Further investigation and development of new broad-spectrum drugs is important for improved treatment of patients with epilepsy and other neurological and psychiatric disorders.
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PMID:Pharmacological management of epilepsy: recent advances and future prospects. 1877 17

Lennox-Gastaut Syndrome (LGS) is a severe form of epilepsy that usually starts in early to mid childhood and is characterized by multiple seizure types, abnormal electroencephalogram with slow spike-and-wave discharges and cognitive problems. Numerous approaches are currently used to treat LGS, including use of conventional antiepileptic drugs (most commonly sodium valproate, lamotrigine and topiramate), other drug interventions (corticosteroids and intravenous immunoglobulin) and nonpharmacologic treatments (ketogenic diet, corpus callosotomy and vagus nerve stimulation). Rufinamide is the most recent antiepileptic drug to have shown efficacy in the treatment of LGS. Despite the variety of therapeutic options, there have been only five double-blind, placebo-controlled clinical trials of antiepileptic drugs in LGS and none of these were head-to-head comparison trials. The evidence supporting the use of available treatments for LGS is, therefore, not robust. Here, we review the evidence supporting the use of specific therapies in LGS and provide recommendations on how to set appropriate treatment goals, select treatments and minimize polypharmacy. A suggested treatment algorithm is presented and discussed. Sodium valproate is recommended for first-line therapy; if seizures persist, alternative interventions should be trialed on an individually tailored basis.
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PMID:Treatment of Lennox-Gastaut Syndrome (LGS). 1921 Dec 83

Rufinamide, a triazole derivative that is structurally distinct from currently marketed antiepileptic drugs (AEDs), is in development for the adjunctive treatment of Lennox-Gastaut syndrome (LGS) in children and adults. Rufinamide is well absorbed after oral administration, demonstrates low protein binding, and is metabolized by enzymatic hydrolysis without involvement of cytochrome P450 enzymes, conferring a low drug interaction potential. In a randomized, double-blind trial involving 138 adult and pediatric patients with LGS, compared with placebo, rufinamide 45 mg/kg/day resulted in significantly superior reductions in drop attacks (median change -42.5% vs +1.4% with placebo) and total seizures (-32.1% vs -11.7% with placebo), accompanied by significantly higher responder rates. These results are comparable with findings reported for other AEDs in randomized, controlled clinical trials in patients with LGS. Rufinamide produced statistically significant seizure reduction which was maintained during long-term therapy and accompanied by good tolerability. The most frequently reported adverse events from a pooled safety database evaluating short- and long-term therapy were headache (22.9% and 29.5%), dizziness (15.5% and 22.5%) and fatigue (13.6% and 17.7%). Rufinamide therefore presents a favorable efficacy and tolerability profile and is a promising candidate for the adjunctive therapy of LGS.
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PMID:Role of rufinamide in the management of Lennox-Gastaut syndrome (childhood epileptic encephalopathy). 1930 May 35


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