Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats

Gáll, Zsolt; Vancea, Szende; Szilágyi, Tibor; Gáll, Orsolya; Kolcsár, Melinda

doi:10.1016/j.ejps.2014.12.012

Cited by 15 publications

(6 citation statements)

References 29 publications

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“…In this study, rufinamide at 5 µM was used. The mean plasma concentration of rufinamide between 1 and 9 within 12 h after administration is about 70 µM, and rufinamide shows high intracerebral transferability [18] [19]. Therefore, we thought that rufinamide would be suitable for SMA treatment.…”

Section: Discussionmentioning

confidence: 98%

The Effects of Rufinamide on <i>in Vitro</i> Spinal Muscular Atrophy Model

Ando¹,

Sato²,

Funato³

et al. 2019

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Spinal muscular atrophy (SMA) is devastating genetic disease characterized by progressive loss of motor neuron and skeletal muscle weakness. SMA is the most common lethal genetic disease in infancy. SMA is caused by deletion or mutation of SMN1 gene and subsequent lack of SMN protein. Our purpose in this study was to evaluate the therapeutic potential of rufinamide, an antiepileptic drug. In this study, SMA patient-derived fibroblasts and differentiated spinal motor neurons (MNs) using SMA patient-derived iPSCs were used as in vitro SMA model. SMN mRNA was significantly increased by addition of rufinamide in type III SMA patient-derived fibroblasts. Furthermore, rufinamide stimulated neurite elongation in type III SMA patient derived-iPSCs-MNs. In contrast of the result using type III SMA patient-derived fibroblasts, the expression level of SMN mRNA was not changed after rufinamide treatment in type I SMA patient-derived fibroblasts, and rufinamide did not affect neurite outgrowth in type I SMA patients derived-iPSCs-MNs. These findings indicate that rufinamide may be one of the potential candidate drugs for mild type of SMA.

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Section: Discussionmentioning

confidence: 98%

The Effects of Rufinamide on <i>in Vitro</i> Spinal Muscular Atrophy Model

Ando¹,

Sato²,

Funato³

et al. 2019

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“…In dosing, safe, effective, and non‐toxic doses of ASMs for chronic use were selected in experimental studies in rats. The following doses were used: ZNS 100 mg/kg/g, STM 100 mg/kg/g, LCM 10 mg/kg/g, CLB 50 mg/kg/g, and RUF 5 mg/kg/g (Brandt et al, 2006; Gall et al, 2015; Ichimaru et al, 1987; Kumar et al, 2018; Manthey et al, 2005). The sample size was determined in the G‐Power 3.1.9.2 package program.…”

Section: Methodsmentioning

confidence: 99%

An investigation of the effects of chronic zonisamide, sultiam, lacosamide, clobazam, and rufinamide anti‐seizure medications on foliculogenesis in ovarian tissue in prepubertal non‐epileptic rats

Kart

Gürgen

Eyüboğlu

et al. 2022

Intl J of Devlp Neuroscience

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“…After type C discharges, there is usually a period of marked postictal suppression, both electrophysiologically and behaviorally, for several seconds to minutes. Rufinamide (50mg/kg, roughly corresponding to serum levels in therapeutic conditions 40,41 ) markedly decreases type B and C, but not type A discharges. Type A discharges are even increased, presumably ascribable to the "truncated" type B and type C discharges and suggestive of the ultimate ineffectiveness of rufinamide on the ultrashort bursts or depolarization.…”

Section: Rufinamide Is Distinctively Effective Against Swds In Vivomentioning

confidence: 97%

How Can an Na⁺ Channel Inhibitor Ameliorate Seizures in Lennox–Gastaut Syndrome?

Lin

Lai

Chou

et al. 2021

Annals of Neurology

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Objective Lennox–Gastaut syndrome (LGS) is an epileptic encephalopathy frequently associated with multiple types of seizures. The classical Na+ channel inhibitors are in general ineffective against the seizures in LGS. Rufinamide is a new Na+ channel inhibitor, but approved for the treatment of LGS. This is not consistent with a choice of antiseizure drugs (ASDs) according to simplistic categorical grouping. Methods The effect of rufinamide on the Na+ channel, cellular discharges, and seizure behaviors was quantitatively characterized in native neurons and mammalian models of epilepsy, and compared with the other Na+ channel inhibitors. Results With a much faster binding rate to the inactivated Na+ channel than phenytoin, rufinamide is distinctively effective if the seizure discharges chiefly involve short bursts interspersed with hyperpolarized interburst intervals, exemplified by spike and wave discharges (SWDs) on electroencephalograms. Consistently, rufinamide, but not phenytoin, suppresses SWD‐associated seizures in pentylenetetrazol or AY‐9944 models, which recapitulate the major electrophysiological and behavioral manifestations in typical and atypical absence seizures, including LGS. Interpretation Na+ channel inhibitors shall have sufficiently fast binding to exert an action during the short bursts and then suppress SWDs, in which cases rufinamide is superior. For the epileptiform discharges where the interburst intervals are not so hyperpolarized, phenytoin could be better because of the higher affinity. Na+ channel inhibitors with different binding kinetics and affinity to the inactivated channels may have different antiseizure scope. A rational choice of ASDs according to in‐depth molecular pharmacology and the attributes of ictal discharges is advisable. ANN NEUROL 2021;89:1099–1113

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Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats

Cited by 15 publications

References 29 publications

The Effects of Rufinamide on <i>in Vitro</i> Spinal Muscular Atrophy Model

The Effects of Rufinamide on <i>in Vitro</i> Spinal Muscular Atrophy Model

An investigation of the effects of chronic zonisamide, sultiam, lacosamide, clobazam, and rufinamide anti‐seizure medications on foliculogenesis in ovarian tissue in prepubertal non‐epileptic rats

How Can an Na⁺ Channel Inhibitor Ameliorate Seizures in Lennox–Gastaut Syndrome?

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Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats

Cited by 15 publications

References 29 publications

The Effects of Rufinamide on &lt;i&gt;in Vitro&lt;/i&gt; Spinal Muscular Atrophy Model

The Effects of Rufinamide on &lt;i&gt;in Vitro&lt;/i&gt; Spinal Muscular Atrophy Model

An investigation of the effects of chronic zonisamide, sultiam, lacosamide, clobazam, and rufinamide anti‐seizure medications on foliculogenesis in ovarian tissue in prepubertal non‐epileptic rats

How Can an Na+ Channel Inhibitor Ameliorate Seizures in Lennox–Gastaut Syndrome?

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The Effects of Rufinamide on <i>in Vitro</i> Spinal Muscular Atrophy Model

The Effects of Rufinamide on <i>in Vitro</i> Spinal Muscular Atrophy Model

How Can an Na⁺ Channel Inhibitor Ameliorate Seizures in Lennox–Gastaut Syndrome?