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Due to the complex pathophysiology of AD (Alzheimer's Disease), there are currently no effective clinical treatments available, except for acetylcholinesterase inhibitors. However, CREB (cyclic AMP-responsive element binding protein) has been identified as the critical factor for the transcription in memory formation. Understanding the effect of potential drugs on the CREB pathway could lead to the development of new therapeutic molecules. Rufinamide has shown promise in improving memory in animal models, and these effects may be associated with modulation of the CREB pathway, however, this has not been previously reported. Thus, the present study aimed to determine the involvement of the CREB pathway in the cognitive improvement effects of rufinamide in STZ (streptozotocin) induced mouse model of dementia. Administration of STZ [3 mg/kg, i.c.v. (intracerebroventricular) bilaterally] significantly impaired cognitive performance in step-down passive avoidance and Morris water maze tests in animals, reduced brain endogenous antioxidant levels (GSH, superoxide dismutase, and catalase), and increased marker of brain oxidative stress [TBARS (thiobarbituric acid reactive substances)] and inflammation [IL-1β (Interleukin-1 beta), IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor alpha) and NF-κB (Nuclear factor kappa B)], along with neurodegeneration. These effects were markedly reversed by rufinamide (50 and 100 mg/kg) when administered to STZ animals. However, the pre-treatment with the CREB inhibitor (666-15) in STZ and rufinamide-administered animals neutralized the beneficial influence of rufinamide. Our data suggest that rufinamide, acting via CREB signaling, reduced oxidative stress and inflammatory markers while elevating anti-oxidant levels. Our study has established that rufinamide may act through CREB signaling in an investigational AD model, which could be crucial for developing new treatments beneficial in progressive neurological disorders. [ABSTRACT FROM AUTHOR]

The global health concern of pharmacoresistant epilepsy necessitates innovative therapeutic strategies. Drug resistance often arises due to complex pharmacokinetic challenges. Beta-cyclodextrin, known for enhancing drug solubility and stability, offers a potential solution for improving the efficacy of antiseizure medications. This study aims to investigate the impact of beta-cyclodextrin-complexed rufinamide on seizure-like activity using an in vitro model of temporal lobe epilepsy.

Background: The goal of this study was to develop and validate a UPLC-MS/MS method for simultaneous measurement of 13 AEDs, including carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, topiramate, primidone, zonisamide, gabapentin, lacosamide, perampanel, pregabalin, rufinamide, and vigabatrin, in whole blood samples. Methods: A UPLC-MS/MS method for simultaneous determination of 13 AEDs in whole blood was developed, and validation was conducted for accuracy, precision, limit of quantification (LOQ), matrix effect, and stability. Our method was compared to two different hospitals using UPLC-MS/MS. Results: All AEDs exhibited linearity across the AMR (analytical measurement range), with R² values ranging from 0.994 to 1.000. The imprecision and inaccuracy for low and high quality control (QC) levels were within an acceptable range, with the coefficient of variation (CV) < 15%. The LOQ was 0.62 μg/mL for carbamazepine, 1.61 μg/mL for oxcarbazepine, 1.30 μg/mL for lamotrigine, 13.20 μg/mL for levetiracetam, 1.26 μg/mL for topiramate, 1.01 μg/mL for primidone, 1.59 μg/mL for zonisamide, 1.09 μg/mL for lacosamide, 1.61 μg/mL for gabapentin, 0.50 μg/mL for pregabalin, 0.07 ng/mL for perampanel, 3.00 μg/mL for rufinamide, and 2.06 μg/mL for vigabatrin. All AEDs demonstrated acceptable assay parameters for carryover, stability, and matrix effects. Moreover, the assay showed satisfactory results compared to two different hospitals with a bias of less than 15%. Conclusions: We successfully developed and validated a fast and robust UPLC-MS/MS method for routine therapeutic drug monitoring of thirteen antiepileptic drugs simultaneously. [ABSTRACT FROM AUTHOR]

Pentylenetetrazole- (PTZ)-induced kindling is a broadly used experimental model to evaluate the impact of antiseizure drugs and their novel combination on seizure progression. The current study aimed to evaluate the anti-kindling effects of ivermectin (IVM) and rufinamide (RUFI) alone and their combination with vitamin E. The mice were administered 11 injections of PTZ (40 mg/kg) followed by assessment for anxiety-like behavior and cognitive abilities in a series of behavior tests with subsequent brain isolation for biochemical and histopathological evaluation. The outcomes showed a marked protection by IVM + RUFI (P<0.001) from kindling progression, anxiety-like behavior and cognitive deficit. However, additional supplementation with vitamin E worked superior to duo therapy as these mice were noted to be most fearless to visiting open, illuminated and elevated zones of open field, light/dark and elevated-plus maze (P<0.0001). Further, they showed marked remembrance of the familiar milieu in y-maze (P<0.01) and novel objection recognition (P<0.05) tests. Additionally, their recollection of aversive stimuli in passive avoidance and spatial memory in Morris water maze were evident (P<0.0001), in comparison to kindled mice. The IVM + RUFI duo therapy and its co-administration with vitamin E prevented kindling-triggered oxidative stress in brains and neuronal damage in hippocampus. We conclude that the benefits of the co-administration of vitamin E might be the results of antioxidant and anti-inflammatory effects of vitamin E which might be potentiating the antiseizure effects of RUFI and GABA-A modulating potential by ivermectin. [ABSTRACT FROM AUTHOR]

Background. Lennox–Gastaut syndrome (LGS) is a classic developmental and epileptic encephalopathy with a debut in childhood, characterized by resistance to therapy, a severe course, and an unfavorable prognosis. Due to the existing difficulties in treatment of LGS, hopes are pinned on development of new antiepileptic drugs with fundamentally different mechanisms of action, aimed specifically at the treatment of this severe form of epilepsy.Rufinamide (Inovelon®) is a new antiepileptic drug registered in the Russian Federation for use in the adjunctive therapy of LGS in patients older than 1 year. The main mechanism of action of rufinamide is the restriction of neuronal discharges associated with the blocking effect on sodium channels (regulation of sodium channels activity by increasing duration of their inactive state), and stabilization of neuronal membranes. The drug has a number of advantages concernung pharmacokinetic parameters and efficacy (including a wide spectrum of antiepileptic activity, good oral absorption, absence of active metabolites, urinary excretion, low affinity for plasma proteins, biotransformation without cytochrome P450 isoenzymes, low risk of drug interactions) and fairly good tolerability. The daily dose of rufinamide varies from 600 mg (with simultaneous administration of valproate) to 1000 mg (if the patient does not take valproate) in children over 4 years of age with a body weight of less than 30 kg and up to 2200–3200 mg in children over 4 years of age with a body weight of more than 30 kg and in adults; in children under 4 years of age, the maximum daily dose in combination with valproate is 30 mg/kg, and without valproic acid – 45 mg/kg.Aim. To analyze the efficacy and tolerability of rufinamide in the treatment of epilepsy based on the long-term experience of using the drug in the Svt. Luka’s Association of Medical Institutions.Materials and methods. We observed 64 patients aged from 1.5 to 26 years (44 men, 20 women) treated with rufinamide (Inovelon®). Among them, the structural etiology LGS was diagnosed in 36 patients, the genetic and presumably genetic etiology LGS – in 28. In all cases, rufinamide was used in accordance with approved indications as an additional antiepileptic drug, more often in combination with valproate, topiramate, levetiracetam or lamotrigine. Titration of the drug was carried out according to the recommendations in the instructions for use, up to a therapeutic dose that ranged from 200 to 1600 mg/day (in most cases from 400 to 1200 mg/day), depending on age and concomitant therapy.Results and conclusion. Remission of all types of seizures was registered in 17 (26.6 %) patients, and a decrease in the incidence of seizures by more than 50 % was recorded in 28 (43.8 %) patients. Of them, 13 patients demonstrated reduction in seizures frequency by more than 75–90 % and remission of one of several types of seizures. In general, the therapeutic effect (reduction of seizures frequency by at least 50 %) was achieved in 45 (70.3 %) of 64 patients. A decrease in seizures frequency of by at least 50 % was observed in 8 (12.5 %) patients; in 10 (15.6 %) patients, rufinamide therapy was not effective; in 1 (1.56 %) case an aggravation of bilateral convulsive seizures was noted when rufinamide was administered.In most cases, rufinamide is well tolerated. Our patients had side effects in 10 (15.6 %) cases. Only in 2 (3.1 %) cases, rufinamide was withdrawn directly due to side effects (the reason for withdrawal in these cases was an allergic reaction and psychosis).The retention rate for therapy lasting 1 year or more is 65.6 % (42 of 64 patients).Thus, our data have demonstrated efficacy and good tolerability of rufinamide in treating epileptic seizures associated with LGS, confirming numerous literature data. However, in our analysis, a higher rate of seizure remission was obtained, although we have included patients with mainly resistant forms of epilepsy in the analysis.

Resveratrol is a polyphenolic phytocompound known to possess anxiolytic-like effects but its impact on central gammaaminobutyric acid (GABA) modulation has never been explored. The purpose of this study was to analyze the anxiolytic-like effects of resveratrol alone and in combination with rufinamide, an antiepileptic drug which has never been studied for its anxiolytic potential. The BALB/c mice were tested in a battery of behavior testing after administration of resveratrol (50 mg/kg) and rufinamide (50 mg/kg) alone and in combination. Moreover, molecular docking studies were also carried out to understand the interaction of resveratrol and rufinamide with GABA aminotransferase, GABA receptor and GABA-A transporter type 1. Resveratrol alone exerted notable anxiolytic-like effects and improved outcomes in few experiments but rufinamide alone did not yield any beneficial outcomes. However, the animal co-administered with resveratrol and rufinamide behaved exceptionally well (p<0.05) and preferred open, illuminated and exposed areas of open field, light/dark and elevated plus maze. Further, these animals showed reduced anxiety towards anxiogenic stimuli i.e. holes and marbles in hole board and marble bury tests, respectively. Resveratrol and rufinamide showed moderate to strong binding affinities with GABA proteins, indicating the potential to treat anxiety-like neurological disorders. Moreover, resveratrol and rufinamide were analyzed using molecular docking to determine their interaction with GABA receptors, transporters, and transaminase. The results suggest that their anxiolytic-like effects may be due to inhibiting GABA reuptake transporter 1 protein, leading to increased synaptic levels of GABA neurotransmitter, as seen in stable molecular dynamics results with the 7SK2 GABA transporter protein. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox–Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin. [ABSTRACT FROM AUTHOR]

• LGS is a severe, chronic, complex form of early childhood-onset epilepsy. • ASMs are routinely used for the management of LGS, often as polytherapy. • Safety, drug interactions, and complementary mechanisms of action must be considered. • Rufinamide is an appropriate early add-on ASM for tonic and atonic seizures in LGS. Lennox-Gastaut syndrome (LGS) is a severe, chronic, complex form of early childhood-onset epilepsy characterized by multiple seizure types, generalized slow (≤2.5 Hz) spike-and-wave activity and other electroencephalography abnormalities, and cognitive impairment. A key treatment goal is early seizure control, and several anti-seizure medications (ASMs) are available. Due to the low success rate in achieving seizure control with monotherapy and an absence of efficacy data supporting any particular combination of ASMs for treating LGS, a rational approach to selection of appropriate polytherapy should be applied to maximize benefit to patients. Such "rational polytherapy" involves consideration of factors including safety (including boxed warnings), potential drug–drug interactions, and complementary mechanisms of action. Based on the authors' clinical experience, rufinamide offers a well-considered first adjunctive therapy for LGS, particularly in combination with clobazam and other newer agents for LGS, and may be particularly useful for reducing the frequency of tonic-atonic seizures associated with LGS. [ABSTRACT FROM AUTHOR]

Lennox–Gastaut syndrome is an epileptic encephalopathy with onset in childhood. The classical triad of diagnostic criteria is well known: 1) presence of various types of refractory epileptic seizures (tonic, atypical absences, myoclonic, tonic/atonic drop attacks, generalized tonic-clonic, focal); 2) cognitive disorders with frequent behavioral disorders (not always evident by the beginning of epileptic seizures); 3) generalized, slow (≤2.5 Hz) spike-wave activity of wakefulness and generalized paroxysmal fast activity on sleep electroencephalogram. Despite the seizure onset usually occurring before the age of 8 (peak at 3–5) years old, the Lennox–Gastaut syndrome is often featured with a lifelong course. Many patients with this syndrome suffer from refractory epilepsy in adulthood, however, not always being provided a proper syndromological diagnosis. Expanding the criteria to diagnose the Lennox–Gastaut syndrome discussed here would allow to choose a proper treatment algorithm. Rufinamide is the drug of the second choice in the adjunctive therapy of epileptic seizures associated with Lennox–Gastaut syndrome. However, a pediatric-to-adult clinic transition of patients with Lennox–Gastaut syndrome may pose some obstacles. Herein, an effective patient management requires not only seizure control, but also improvement of patient's quality of life by influencing cognitive and behavioral issues, sleep disorders, disability (both physical and social), educational problems and employment.

Rufinamide (Rufi) is an antiepileptic drug used to manage Lennox-Gastaut Syndrome and partial seizures. The oral bioavailability of Rufi is less due to its poor solubility and low dissolution rate in the gastrointestinal fluids. This results in less amount of drug reaching the brain following the oral administration of drug. Oral formulations of Rufi are prescribed at a high dose and dosing frequency to increase its distribution to the brain. A Rufi loaded thermoresponsive nasal in situ gel which showed significantly high brain concentrations compared to aqueous suspension of Rufi administered through nasal route was developed by our research group and published. In the current work, we have formulated nanocrystals of Rufi and suspended them in a xyloglucan based thermoresponsive gel to improve the nose-to-brain distribution. The particle size, polydispersity index, and yield (%) of the optimized Rufi nanocrystals were 261.2 ± 2.1 nm, 0.28 ± 0.08, and 89.6 ± 2.0 respectively. The narrow PDI indicates that the manufacturing process is reproducible and reliable. Higher % yield suggested that the method of preparation is efficient. The sol-to-gel transition of in situ gel loaded with Rufi nanocrystals was at 32°C which suggested that the formulation transforms into gel at nasal epithelial temperatures. The nasal pharmacokinetic studies showed that Rufi nanocrystals loaded in situ gel produced higher concentration of the drug in brain (higher brain Cmax) and maintained the drug concentrations for longer duration (higher mean residence time) compared to aqueous suspension of Rufi nanocrystals as well aqueous suspension of Rufi and Rufi loaded in situ gel, reported previously. Nanometric size of the Rufi nanocrystals combined with the in situ gelling properties helped the optimized formulation achieve higher brain distribution and also sustain the drug concentrations in brain for longer duration compared to any of the formulations studied by our research group. [ABSTRACT FROM AUTHOR]

Rufinamide (Rufi) is an antiepileptic drug used to manage Lennox-Gastaut Syndrome and partial seizures. The oral bioavailability of Rufi is less due to its poor solubility and low dissolution rate in the gastrointestinal fluids. This results in less amount of drug reaching the brain following the oral administration of drug. Oral formulations of Rufi are prescribed at a high dose and dosing frequency to increase its distribution to the brain. A Rufi loaded thermoresponsive nasal in situ gel which showed significantly high brain concentrations compared to aqueous suspension of Rufi administered through nasal route was developed by our research group and published. In the current work, we have formulated nanocrystals of Rufi and suspended them in a xyloglucan based thermoresponsive gel to improve the nose-to-brain distribution. The particle size, polydispersity index, and yield (%) of the optimized Rufi nanocrystals were 261.2 ± 2.1 nm, 0.28 ± 0.08, and 89.6 ± 2.0 respectively. The narrow PDI indicates that the manufacturing process is reproducible and reliable. Higher % yield suggested that the method of preparation is efficient. The sol-to-gel transition of in situ gel loaded with Rufi nanocrystals was at 32°C which suggested that the formulation transforms into gel at nasal epithelial temperatures. The nasal pharmacokinetic studies showed that Rufi nanocrystals loaded in situ gel produced higher concentration of the drug in brain (higher brain Cmax) and maintained the drug concentrations for longer duration (higher mean residence time) compared to aqueous suspension of Rufi nanocrystals as well aqueous suspension of Rufi and Rufi loaded in situ gel, reported previously. Nanometric size of the Rufi nanocrystals combined with the in situ gelling properties helped the optimized formulation achieve higher brain distribution and also sustain the drug concentrations in brain for longer duration compared to any of the formulations studied by our research group.

The new antiepileptic drugs perampanel, retigabine, rufinamide and stiripentol have been recently approved for different epilepsy types. Being them an innovation in the antiepileptics armamentarium, a lot of investigations regarding their pharmacological properties are yet to be performed. Besides, considering their broad anticonvulsant activities, an extension of their therapeutic indications may be worthy of investigation, especially regarding other seizure types as well as other central nervous system disorders. Although different liquid chromatographic (LC) methods coupled with ultraviolet, fluorescence, mass or tandem-mass spectrometry detection have already been developed for the determination of perampanel, retigabine, rufinamide and stiripentol, new and more cost-effective methods are yet required. Therefore, this review summarizes the main analytical aspects regarding the liquid chromatographic methods developed for the analysis of perampanel, retigabine (and its main active metabolite), rufinamide and stiripentol in biological samples and pharmaceutical dosage forms. Furthermore, the physicochemical and stability properties of the target compounds will also be addressed. Thus, this review gathers, for the first time, important background information on LC methods that have been developed and applied for the determination of perampanel, retigabine, rufinamide and stiripentol, which should be considered as a starting point if new (bio)analytical techniques are aimed to be implemented for these drugs.

Objective: The Patient Information Leaflet (PIL) is an authoritative document that all people with epilepsy in the EU receive when prescribed antiseizure medication (ASM). We undertook the first independent, comprehensive assessment to determine how understandable they are. Regulators state that when patients are asked comprehension questions about them, ≥80% should answer correctly. Also, recommended is that PILs have a maximum reading requirement of US grade 8. Methods: Study 1: We obtained 140 current ASM PILs written in English. "Readability" was assessed using four tests, with and without adjustment for influence of familiar, polysyllabic words. A total of 179 online materials on epilepsy were also assessed. Study 2: Two PILs from Study 1 were randomly selected (Pregabalin Focus; Inovelon) and shown to 35 people from the UK epilepsy population. Their comprehension was assessed. Study 3: To understand whether the student population provides an accessible alternative population for future examination of ASM PILs, Study 3 was completed, using the same methods as Study 2, except that participants were 262 UK university students. Results: Study 1: No PIL had a reading level of grade 8. Median was grade 11. Adjusting for context, the PILs were still at grade 10.5. PILs for branded ASMs were most readable. PILs were no more readable than (unregulated) online materials. Study 2: Users struggled to comprehend the PILs' key messages. The eight questions asked about pregabalin were typically answered correctly by 54%. For Inovelon, it was 62%. Study 3: Most student participants comprehended the PILs' key messages. The questions about Inovelon were answered correctly by 90%; for pregabalin it was 86%. Significance: This is the first independent and comprehensive examination of ASM PILs. It found that PILs being used fail to meet recommendations and regulatory requirements and risk not being understandable to a substantial proportion of users. In finding that people from the epilepsy population differ markedly in comprehension of PILs compared to students, this study highlights the importance of completing user testing with the target population. [ABSTRACT FROM AUTHOR]

Purpose: To assess the short-term and long-term comparative efficacy and safety of ASMs for Lennox-Gastaut syndrome (LGS).Methods: Following a systematic literature search, randomized controlled trial (RCT) and open-label extension (OLE) studies on LGS comparing ASMs with placebo or other ASMs were included. ≥50% reduction in drop seizure frequency from baseline and occurrence of treatment-emergent adverse events (TEAEs) were the primary efficacy and safety outcomes. For short-term outcomes, a network meta-analysis (NMA) reporting odds ratio (OR) with 95% confidence intervals (CIs) and hierarchy of competing interventions [surface under the cumulative ranking curve(SUCRA)] was done. Long-term outcomes were reported as proportion with 95% CIs using the random-effects model.Results: Fifteen studies including 1263 participants with LGS (aged 2-54years) receiving any of six ASMs [cannabidiol (CBD), clobazam (CLB), felbamate (FLB), lamotrigine (LTG), rufinamide (RFM), topiramate (TPM)] or placebo were included. High-dose CLB (1.0 mg/kg/day; CLB_H) [OR: 4.9; 95% CI: 2.3-10.8] was significantly associated with ≥50% reduction in drop seizure frequency as compared with placebo, and achieved the highest-ranking probability (0.89) based on SUCRA values (although there was an overlap between confidence intervals of effect sizes of CLB, RFM and CBD), while high-dose CBD (20 mg/kg/day; CBD_H) [OR: 3.8; 95% CI:1.6-9.0] had significantly higher odds for occurrence of any TEAEs and had the highest-ranking probability (0.85). Furthermore, the long-term treatment with CLB [78%; 95% CI: 70-85%] was associated with a significantly higher proportion of patients with reduction in drop-seizures, and long-term use of CBD [96%; 95% CI: 95-98%] was associated with a higher frequency of TEAEs.Conclusion: The study findings suggest that CLB_H, CBD and RFM are the most efficacious and safest in terms of both short and long-term outcomes with CLB_H probably leading the hierarchy. Future head-to-head trials comparing these ASMs are needed. [ABSTRACT FROM AUTHOR]

Objectives: Two optimized and validated high performance liquid chromatography (HPLC) and spectrophotometric methods are proposed. The developed methods were quantified with high sensitivity, accuracy, and precision at low concentrations to determine rufinamide (RUF) in active pharmaceutical ingredients (API) and pharmaceutical preparations. Materials and Methods: HPLC method was developed using a base deactivated silica Hypersil C18 column and a combination of methanol: acetonitrile: water (15: 10: 75, v/v/v) as the mobile phase and detected at 210 nm. A reaction of RUF with sodium nitrite and hydrochloric acid occurred, absorbed maximally at 385 nm was extended to develop a ultraviolet (UV)-visible spectrophotometric method to determine RUF in API and pharmaceutical preparations. Results: Different analytical validation parameters, including specificity, linearity, accuracy, precision, the limit of detection, quantification, ruggedness, and robustness, were determined as per International Conference on Harmonization guidelines. The linearity range of RUF was 0.15- 3.5 and 10-100 μg/mL for HPLC and spectrophotometric methods, respectively. Conclusion: The proposed investigations were valuable for drug monitoring and regular analysis of RUF in quality control and research laboratories. Moreover, the accuracy and precision obtained with the UV-visible spectrophotometer implied that it could be a cheap, easy, and alternative method, while HPLC could be sensitive to determine RUF at low concentration levels. [ABSTRACT FROM AUTHOR]

Rufinamide is used presently to treat Lenaux–Gastaut syndrome. A full factorial design and desirability approach was investigated for the optimization of hydrolytic stress via response surface curves (RSCs). The degradation impurities were identified and resolved using reversed‐phase high‐performance liquid chromatography (RP‐HPLC) on the Qualisil® BDS C8 column. Acetonitrile–water (29:71, v/v) was optimized for the mobile phase and used at a flow rate of 1.0 ml/min with detection at a wavelength of 230 nm. Rufinamide showed appreciable susceptibility to hydrolysis under acidic and alkaline stress, and substantial degradation in the neutral condition. It degraded much less under oxidative stress. Exposure towards thermal and photolytic stress conditions indicated appreciable stability. The developed method was subjected to validation as per the recommendations of the International Conference on Harmonization. The proposed method showed no influence from the excipients and the degradation products. As well as good precision and accuracy in determination, the method showed a linear response between 2 and 12 μg ml−1. The method was extended for determination in a human plasma sample, which resulted in excellent recovery without interference from matrix effects. The combined use of desirability and design for the optimization of acidic and alkaline hydrolytic stress led to simple and rapid analysis. [ABSTRACT FROM AUTHOR]

In the past few decades, click chemistry (CuAAC reaction) has seen tremendous development both in terms of catalyst designing and method development because 1,2,3‐triazoles products have shown enormous applications in various fields. The sought after azide‐alkyne cycloaddition reaction catalyzed by smaller‐sized (∼7 nm) Cu(I/II) oxide nanoparticles (CuI/IIO NPs) supported by thiol‐functionalized cellulose provided triazole products in excellent yields (90–98%) with remarkable 1,4‐regioselectivity, including the 10 g scale synthesis of a rufinamide drug intermediate. The possible reasons for this exceptional activity are the higher ratio of Cu (I), along with the smaller‐sized and homogeneously dispersed colloidal nature of CuI/IIO NPs. Most importantly, the reaction underwent industrially friendly greener conditions such as aqueous medium, room temperature, and no additives, etc. suggesting promising for practical applications. The as‐prepared catalyst was recycled and reused up to 5 cycles by simply filtering the precipitate 1,2,3‐triazoles products without losing significant activity. [ABSTRACT FROM AUTHOR]

Introduction: Rufinamide is an antiseizure medication that acts through sodium channels and is found to be efficacious in patients with Lennox Gastaut syndrome (LGS). However, no systematic review has been conducted in LGS patients to provide an estimate of the efficacy and safety of rufinamide.Methods: Different electronic databases were searched for articles describing the use of rufinamide in patients with LGS. For determining primary efficacy outcomes as compared to placebo, we included only studies comparing the efficacy of rufinamide with placebo in LGS patients. We performed an additional analysis to include other uncontrolled studies with a minimum sample size of 20 to provide a more comprehensive estimate of efficacy.Results: A total of ten studies included 557 patients. Out of them, five studies were placebo-controlled, enrolling a total of 265 patients in the rufinamide group and 203 patients in the placebo group. The average percentage reduction in total seizure frequency per 28 days during the double-blind phase was 29.3% in the rufinamide group compared with 8.3% in the placebo group (difference between the two groups was 20.9%, 95%CI-14.4%-27.3%, p <0.00001). Even for individual seizure types like tonic-clonic seizures, atypical absence seizures, atonic seizures, focal seizures, and myoclonic seizures, rufinamide was more efficacious than placebo(p<0.00001). The number of patients with at least one treatment-emergent adverse effects was significantly higher in rufinamide treated patients (60.2%vs50.7%, p=0.02, RR-1.24(1.03,1.51).Conclusion: Rufinamide is efficacious as adjunctive therapy in patients with LGS in terms of reduction in total seizure frequency and has mild adverse reaction. [ABSTRACT FROM AUTHOR]

Ganna Balagura,1,2 Antonella Riva,2 Francesca Marchese,2 Alberto Verrotti,3 Pasquale Striano1,2 1Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Italy; 2Pediatric Neurology and Muscular Diseases Unit, IRCCS ‘G. Gaslini’ Institute, Genoa, Italy; 3Department of Pediatrics, University of L’Aquila, L’Aquila, ItalyCorrespondence: Pasquale Striano Email strianop@gmail.comAbstract: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset, developmental epileptic encephalopathy, with different etiologies and co-morbidities. Seizure treatment in LGS represents a major challenge; new antiepileptic drugs (AEDs) are developed to especially address seizures resulting in high morbidity and mortality, such as drop seizures. Rufinamide (RFN) is one of the latest AEDs licensed for patients with LGS. Its mechanism of action involves sodium channels in a way that is unrelated to other AEDs. Here we discuss the use of adjunctive RFN in children and adolescents with LGS and its efficacy and safety profile, based on a systematic literature review. RFN shows a very favorable profile in terms of adverse events and drug-interactions in children. It is particularly effective on tonic-atonic seizures and spasms, impacting on the quality of life of the patients. Further studies are needed to clarify the interaction profile with the newest AEDs for LGS and to assess correlations between the etiology of LGS and drug response to individualize treatment and maximize efficacy.Keywords: rufinamide, Lennox-Gastaut, epilepsy, children

Summary Objective Drug development for patients with Lennox‐Gastaut syndrome (LGS) is based on clinical trials that use drop seizure counts. However, such counts do not assess total seizure burden and affect a patient's quality of life (QoL). In this post hoc analysis, we evaluated two novel seizure efficacy parameters related to QoL in pediatric patients with LGS, using seizure diary data from rufinamide Study 303 (NCT01405053). Methods Study 303 was a phase III, multicenter, randomized, controlled, open‐label study involving patients aged ≥1 to

In 2004, the US FDA approved Rufinamide, an anti-epileptic drug under the brand name Banzel®. In 2015, Banzel® received approval for its use in pediatric patients (ages 1–4 years). Rufinamide shows low oral bioavailability due to a low dissolution rate resulting in less of the drug reaching the brain. This has led to the high dose and dosing frequency of Rufinamide. In this work, using the principle of design of experiments (DoE), we have formulated Rufinamide-loaded chitosan nanoparticles and suspended them in a solution of a thermoresponsive polymer–tamarind seed xyloglucan to form a nasal in situ gel for direct nose to brain delivery of Rufinamide. The nanoparticles were characterized for particle size, entrapment efficiency, zeta potential, and physical stability. The in situ gel formulations were characterized for rheological properties, stability, and in vivo plasma and brain pharmacokinetics. Pharmacokinetic parameters were computed for aqueous suspension of nanoparticles and in situ gelling formulation for nanoparticles and compared with the pharmacokinetic parameters of an aqueous suspension of plain Rufinamide. The percentage of direct transport efficiency (% DTE) and direct transport percentage (%DTP) values were calculated for all the formulations. The optimized nanoparticle formulation showed a size of 180 ± 1.5 nm, a zeta potential of 38.3 ± 1.5 mV, entrapment efficiency of 75 ± 2.0%, and drug loading of 11 ± 0.3%. The in situ gelling formulation of nanoparticles showed a solution to the gel transition temperature of 32°C. The %DTE values for aqueous suspension of nanoparticles and in situ gelling formulation for nanoparticles were 988.5 and 1177.3 and the %DTP values were 86.06 and 91.5 respectively.

The new antiepileptic drugs perampanel, retigabine, rufinamide and stiripentol have been recently approved for different epilepsy types. Being them an innovation in the antiepileptics armamentarium, a lot of investigations regarding their pharmacological properties are yet to be performed. Besides, considering their broad anticonvulsant activities, an extension of their therapeutic indications may be worthy of investigation, especially regarding other seizure types as well as other central nervous system disorders. Although different liquid chromatographic (LC) methods coupled with ultraviolet, fluorescence, mass or tandem-mass spectrometry detection have already been developed for the determination of perampanel, retigabine, rufinamide and stiripentol, new and more cost-effective methods are yet required. Therefore, this review summarizes the main analytical aspects regarding the liquid chromatographic methods developed for the analysis of perampanel, retigabine (and its main active metabolite), rufinamide and stiripentol in biological samples and pharmaceutical dosage forms. Furthermore, the physicochemical and stability properties of the target compounds will also be addressed. Thus, this review gathers, for the first time, important background information on LC methods that have been developed and applied for the determination of perampanel, retigabine, rufinamide and stiripentol, which should be considered as a starting point if new (bio)analytical techniques are aimed to be implemented for these drugs. [Display omitted] • Stiripentol, retigabine, rufinamide and perampanel are new antiepileptic drugs (AEDs). • Liquid chromatography methods for these AEDs determination are critically discussed. • Main strategies to extract these AEDs from biological samples are herein compared. • Physicochemical properties of these AEDs are critical for methods optimization. [ABSTRACT FROM AUTHOR]

In 2004, the US FDA approved Rufinamide, an anti-epileptic drug under the brand name Banzel®. In 2015, Banzel® received approval for its use in pediatric patients (ages 1–4 years). Rufinamide shows low oral bioavailability due to a low dissolution rate resulting in less of the drug reaching the brain. This has led to the high dose and dosing frequency of Rufinamide. In this work, using the principle of design of experiments (DoE), we have formulated Rufinamide-loaded chitosan nanoparticles and suspended them in a solution of a thermoresponsive polymer–tamarind seed xyloglucan to form a nasal in situ gel for direct nose to brain delivery of Rufinamide. The nanoparticles were characterized for particle size, entrapment efficiency, zeta potential, and physical stability. The in situ gel formulations were characterized for rheological properties, stability, and in vivo plasma and brain pharmacokinetics. Pharmacokinetic parameters were computed for aqueous suspension of nanoparticles and in situ gelling formulation for nanoparticles and compared with the pharmacokinetic parameters of an aqueous suspension of plain Rufinamide. The percentage of direct transport efficiency (% DTE) and direct transport percentage (%DTP) values were calculated for all the formulations. The optimized nanoparticle formulation showed a size of 180 ± 1.5 nm, a zeta potential of 38.3 ± 1.5 mV, entrapment efficiency of 75 ± 2.0%, and drug loading of 11 ± 0.3%. The in situ gelling formulation of nanoparticles showed a solution to the gel transition temperature of 32°C. The %DTE values for aqueous suspension of nanoparticles and in situ gelling formulation for nanoparticles were 988.5 and 1177.3 and the %DTP values were 86.06 and 91.5 respectively. [ABSTRACT FROM AUTHOR]

Background: Rufinamide, a triazole derivative, is a new-generation antiseizure medication with a novel mechanism of action. We evaluated the efficacy and safety of rufinamide treatment in children with epilepsy younger than 4 years at our center. Methods: In this retrospective study, we included children younger than 4 years who had pharmacologically resistant epilepsy and were treated with rufinamide at Boston Children's Hospital between June 2010 and June 2018. Safety and efficacy of rufinamide treatment were assessed immediately prior to initiation of rufinamide and at the last follow-up visit. Responders were defined as patients who had greater than 50% reduction in seizure frequency on follow-up as compared to baseline. Results: We reviewed records of 128 children and included 103 with complete information. Patients consisted of 60 boys (58%), with a median age of 20 months (interquartile range 13-28, range 2-36). Median treatment duration was 15 months, and median rufinamide dosage at the last follow-up was 42 mg/kg/d (interquartile range 34-56). At the last follow-up, seizure frequency decreased (450 vs 90, P<.001) and overall seizure reduction was 54%. Fifty-one patients (49.5%) were responders with 94% seizure reduction, including 20 (19.4%) who achieved seizure freedom. Treatment retention rate at 12 months was 63%. Thirty patients (29%) developed adverse events and 41 patients (39.8%) discontinued rufinamide because of adverse events (15; 14.5%) and lack of efficacy (26; 25%). Conclusion: Rufinamide is effective in reducing seizure frequency in pediatric epilepsy patients younger than 4 years, and overall well tolerated. [ABSTRACT FROM AUTHOR]

Lennox–Gastaut syndrome (LGS) is a childhood epileptic encephalopathy characterized by frequent polymorphic seizures (including tonic axial seizures), pronounced cognitive impairment, typical changes in the electroencephalogram and drug resistance. Since the disease is quite common (accounts for 4–10 % of all childhood epilepsy) and is characterized by various seizures that are frequently resistant to multiple antiepileptic drugs, great hopes are currently centered on the development of novel antiepileptic drugs with principally different mechanisms of action aimed to treat this severe form of epilepsy. Rufinamide (inovelon) is a promising antiepileptic drug for LGS therapy. In 2008, it was approved by the FDA as an adjunctive treatment of seizures associated with LGS in adults and children over 4 years of age. Rufinamide demonstrated its efficacy against both drop seizures (tonic/atonic) and generalized seizures (tonic, atonic and tonic-clonic) in LGS. In January 2015, the drug was approved for use in the Russian Federation for seizures associated with LGS in patients over 4 years of age. Multiple studies have demonstrated high efficacy and good tolerability of rufinamide in children and adults with epilepsy. In this article, we provide a systematic review of the currently available data on the use of rufinamide in the treatment of seizures associated with LGS.

Background. Despite significant advances in epileptology, approximately one-third of epilepsy patients suffer from drug-resistant seizures. Numerous approaches are currently available to treat epilepsy; however, there are still many patients with treatment-resistant epilepsy, in whom surgical treatment is impossible and alternative methods (vagus nerve stimulation and ketogenic diet) are ineffective. Therefore, searching for novel effective antiepileptic drugs (AEDs) is crucial for these patients.Objective: analysis of own data on the efficacy and tolerability of rufinamide in patients with severe forms of epilepsy and seizures typical of Lennox–Gastaut syndrome (LGS).Materials and methods. The study included 31 patients aged between 4 and 26 years (mean age 7.5 years) that received rufinamide (inovelon). The study cohort comprised 21 males and 10 females. Fifteen patients were diagnosed with LGS, whereas 16 patients were diagnosed with structural focal epilepsy with a phenocopy of LGS. Five patients had an evolution of West syndrome to LGS. The majority of patients (n = 22) experienced predominantly axial tonic seizures and epileptic spasms that were considered as indications for introduction of rufinamide. All patients underwent electroencephalography, video-electroencephalography monitoring during wakefulness and sleep, magnetic resonance imaging (MRI) (including high-resolution MRI with special epilepsy protocols when indicated), genetic examination (tandem mass spectrometry, hereditary epilepsy gene panel test and chromosomal microarray analysis) when indicated, and laboratory tests to assess tolerability of antiepileptic drugs.Results. Good therapeutic effect (more than 50 % reduction in seizure frequency) was achieved in 14 (45.2 %) patients. A less than 50 % reduction in seizure frequency occurred in 5 (16.1 %) patients; in 2 of them seizures became shorter and milder without a significant reduction in their frequency. Rufinamide was ineffective in 9 (29 %) patients. Three (9.7 %) patients experienced aggravation (increased seizure frequency) after the introduction of rufinamide. Thus, treatment with rufinamide was effective in 19 (61.3 %) patients. Rufinamide was well tolerated by most of the patients. Side effects were observed in 6 (19 %) participants. Side effects (forced normalization) caused withdrawal of rufinamide in 1 (3.2 %) patient. Currently, 10 (32 %) patients continue to take rufinamide. Sixteen patients received rufinamide for 6 months, 5 patients – for >12 months, and 1 patient – for >2 years.Conclusion. Our findings are consistent with the results obtained by foreign authors in routine clinical practice. In our study, rufinamide was used only in patients with drug-resistant epilepsy that earlier received many of currently available AEDs (both in monotherapy and in combination with other drugs). All study participants were earlier treated with at least three different AEDs that were ineffective. Seven patients received more than 8 AEDs in various combinations. This initial drug resistance should be taken into account when analyzing the data, which can not be extrapolated to patients with unknown drug resistance. We assume that the early introduction of rufinamide (prior to the detection of drug resistance) might have yielded better results.

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within‐patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r2 =.78, P <.0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose‐normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme‐inducing or enzyme‐inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations. [ABSTRACT FROM AUTHOR]