scholarly journals Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Pierandrea Muglia ◽  
Jonas Hannestad ◽  
Christian Brandt ◽  
Steven DeBruyn ◽  
Massimiliano Germani ◽  
...  
Keyword(s):  
Adverse Events ◽  
Antiepileptic Drug ◽  
Synaptic Vesicle ◽  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Unmet Need ◽  
Proof Of Concept ◽  
Treatment Resistant ◽  
Synaptic Vesicle Protein ◽  
Translational Approach

Abstract Therapeutic options for patients with treatment-resistant epilepsy represent an important unmet need. Addressing this unmet need was the main factor driving the drug discovery program that led to the synthesis of padsevonil, a first-in-class antiepileptic drug candidate that interacts with two therapeutic targets: synaptic vesicle protein 2 and GABAA receptors. Two PET imaging studies were conducted in healthy volunteers to identify optimal padsevonil target occupancy corresponding to levels associated with effective antiseizure activity in rodent models. Optimal padsevonil occupancy associated with non-clinical efficacy was translatable to humans for both molecular targets: high (>90%), sustained synaptic vesicle protein 2A occupancy and 10–15% transient GABAA receptor occupancy. Rational dose selection enabled clinical evaluation of padsevonil in a Phase IIa proof-of-concept trial (NCT02495844), with a single-dose arm (400 mg bid). Adults with highly treatment-resistant epilepsy, who were experiencing ≥4 focal seizures/week, and had failed to respond to ≥4 antiepileptic drugs, were randomized to receive placebo or padsevonil as add-on to their stable regimen. After a 3-week inpatient double-blind period, all patients received padsevonil during an 8-week outpatient open-label period. The primary endpoint was ≥75% reduction in seizure frequency. Of 55 patients randomized, 50 completed the trial (placebo n = 26; padsevonil n = 24). Their median age was 36 years (range 18–60), and they had been living with epilepsy for an average of 25 years. They were experiencing a median of 10 seizures/week and 75% had failed ≥8 antiepileptic drugs. At the end of the inpatient period, 30.8% of patients on padsevonil and 11.1% on placebo were ≥75% responders (odds ratio 4.14; P = 0.067). Reduction in median weekly seizure frequency was 53.7% and 12.5% with padsevonil and placebo, respectively (unadjusted P = 0.026). At the end of the outpatient period, 31.4% were ≥75% responders and reduction in median seizure frequency was 55.2% (all patients). During the inpatient period, 63.0% of patients on placebo and 85.7% on padsevonil reported treatment-emergent adverse events. Overall, 50 (90.9%) patients who received padsevonil reported treatment-emergent adverse events, most frequently somnolence (45.5%), dizziness (43.6%) and headache (25.5%); only one patient discontinued due to a treatment-emergent adverse event. Padsevonil was associated with a favourable safety profile and displayed clinically meaningful efficacy in patients with treatment-resistant epilepsy. The novel translational approach and the innovative proof-of-concept trial design maximized signal detection in a small patient population in a short duration, expediting antiepileptic drug development for the population with the greatest unmet need in epilepsy.

scholarly journals First, do no harm: the risks of overtreating children with epilepsy

2007 ◽  
Vol 65 (1) ◽  
pp. 1-4 ◽  
Author(s):  
Eunice Chuang ◽  
Marilisa M. Guerreiro ◽  
Sara Y. Tsuchie ◽  
Angelica Santucci ◽  
Carlos A. M. Guerreiro ◽  
...  
Keyword(s):  
Adverse Events ◽  
Prospective Study ◽  
Antiepileptic Drug ◽  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Seizure Control ◽  
Control Method ◽  
Refractory Epilepsy ◽  
Do No Harm ◽  
A Prospective Study

BACKGROUND: Although overtreatment with antiepileptic drugs contributes to the morbidity associated with epilepsy, many children still are overtreated. OBJECTIVE: To evaluate if the withdrawal of at least one antiepileptic drug (AED) in children with refractory epilepsy using polytherapy enable a better seizure control. METHOD: This was a prospective study. Children with refractory epilepsy using at least two AEDs were included. Once the patient, or guardian, agreed to participate in the study, one or more AED were slowly tapered off. The remaining AEDs dosages could be adjusted as needed, but a new AED could not be introduced. RESULTS: Fifteen patients were evaluated, three girls; ages ranging from 3 to 18 (mean=8.7 years). After at least one AED withdrawal, two (13.5%) patients became seizure free, seizures improved >50% in 5 (33.5%) patients, did not change in 5 (33.5%), and seizure frequency became worse in 3 (20%). Adverse events improved in 12 patients (80%). CONCLUSION: The withdrawal of at least one AED is a valuable option in the treatment of selected children with refractory epilepsy.

scholarly journals The peculiarities of focal epilepsy in pregnant women

2017 ◽  
Vol 98 (5) ◽  
pp. 729-732 ◽  
Author(s):  
Sh Y Melikova
Keyword(s):  
Status Epilepticus ◽  
Sleep Deprivation ◽  
Pregnant Women ◽  
Antiepileptic Drug ◽  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Focal Epilepsy ◽  
Average Duration ◽  
Convulsive Status Epilepticus

Aim. To investigate the peculiarities of focal epilepsy in pregnant women. Methods. 70 pregnant women with symptomatic focal epilepsy during the period from 2013 to 2017 were studied. Results. The average age at the onset of epilepsy was 18.2±0.6 years. The average duration of epilepsy by the time of pregnancy was 6.6±0.7 years. 15 (21.4±4.9%) women remained seizure-free during pregnancy. Seizures during pregnancy were observed in 55 (78.6±4.9%) women: seizure frequency increased in 22 (31.4±5.5%) cases, decreased in 17 (24.3±5.1%), remained unchanged in 8 (11.4±3.8%), in 8 (11.4±3.8%) women the onset of epilepsy occurred during pregnancy. 72.7% of women who were seizure-free for 1 year prior to pregnancy remained seizure-free during pregnancy. In 21 (40.4%) of 52 women with epilepsy diagnosed prior to pregnancy and treated with antiepileptic drugs, the increase of seizure frequency was observed, which can be explained by non-compliance with the regimen and therapy and sleep deprivation in 15 (71.4%) of them. Generalized convulsive status epilepticus during pregnancy was observed in 1 (1.4±1.4%) woman after a sudden withdrawal of the antiepileptic drug. Conclusion. The risk of seizures during pregnancy is lower in women who were seziure-free for 1 year prior to pregnancy; non-compliance with the regimen and therapy and sleep deprivation may lead to worsening of epilepsy during pregnancy.

Synaptic Vesicle Protein 2A as a Novel Pharmacological Target with Broad Potential for New Antiepileptic Drugs

2016 ◽  
pp. 53-81
Author(s):  
Luz Adriana Pichardo-Macías ◽  
Itzel Jatziri Contreras-García ◽  
Sergio R. Zamudio ◽  
Edgar Mixcoha ◽  
Julieta G. Mendoza-Torreblanca
Keyword(s):  
Synaptic Vesicle ◽  
Antiepileptic Drugs ◽  
Synaptic Vesicle Protein ◽  
New Antiepileptic Drugs ◽  
Pharmacological Target ◽  
Vesicle Protein ◽  
Synaptic Vesicle Protein 2A

scholarly journals Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy

2018 ◽  
Vol 18 (4) ◽  
pp. 269-278 ◽  
Author(s):  
Andres M. Kanner ◽  
Eric Ashman ◽  
David Gloss ◽  
Cynthia Harden ◽  
Blaise Bourgeois ◽  
...  
Keyword(s):  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Extended Release ◽  
Focal Epilepsy ◽  
Immediate Release ◽  
Juvenile Myoclonic Epilepsy ◽  
Review Literature ◽  
Treatment Resistant ◽  
New Antiepileptic Drugs ◽  
Frequency Level

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). Methods: 2004 criteria were used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Forty-two articles were included. Recommendations: The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment; rufinamide for Lennox–Gastuat syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic–clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month to 16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6–17 years); oxcarbazepine for TRCFE (1 month to 4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.

scholarly journals A Curious Case of Hypercalcemia

2018 ◽  
Vol 13 (1) ◽  
Author(s):  
Douglas Ian Noboru Motomura ◽  
Paul Allan Cameron
Keyword(s):  
Internal Medicine ◽  
Synaptic Vesicle ◽  
Seizure Frequency ◽  
Clinical Entity ◽  
Medecine Interne ◽  
Diagnostic Algorithms ◽  
Synaptic Vesicle Protein ◽  
First Case ◽  
Synaptic Vesicle Protein 2A ◽  
Inpatient Units

Hypercalcemia is a clinical entity commonly seen on Internal Medicine inpatient units. Through standard diagnostic algorithms, the etiology of most cases can be elucidated. Brivaracetam is a novel anti-epileptic agent that binds synaptic vesicle protein 2A shown to significantly reduce seizure frequency. We describe the first case of hypercalcemia secondary to brivaracetam. Résumé L'hypercalcémie est une entité clinique couramment observée sur les unités d'hospitalisation en médecine interne. Grâce à des algorithmes de diagnostic standard, l'étiologie de la plupart des cas peut être élucidée. Brivaracetam est un nouvel agent anti-épileptique qui lie la protéine de vésicule synaptique 2A montrée pour réduire significativement la fréquence de saisie. Nous décrivons le premier cas d'hypercalcémie secondaire à Brivaracetam.    

scholarly journals The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam

2004 ◽  
Vol 101 (26) ◽  
pp. 9861-9866 ◽  
Author(s):  
B. A. Lynch ◽  
N. Lambeng ◽  
K. Nocka ◽  
P. Kensel-Hammes ◽  
S. M. Bajjalieh ◽  
...  
Keyword(s):  
Antiepileptic Drug ◽  
Binding Site ◽  
Synaptic Vesicle ◽  
Synaptic Vesicle Protein ◽  
Vesicle Protein

Impact of temozolomide chemotherapy on seizure frequency in patients with low-grade gliomas

2011 ◽  
Vol 114 (6) ◽  
pp. 1617-1621 ◽  
Author(s):  
Jonathan H. Sherman ◽  
Krisztina Moldovan ◽  
H. Kwang Yeoh ◽  
Robert M. Starke ◽  
Nader Pouratian ◽  
...  
Keyword(s):  
Antiepileptic Drug ◽  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Intractable Epilepsy ◽  
Age At Diagnosis ◽  
Control Group ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Significant Difference

Object Seizures occur in approximately 80% of patients with low-grade gliomas (LGGs). The majority of patients are treated with anticonvulsant monotherapy; however, many patients require multidrug therapy, or their seizures are refractory to antiepileptic drugs altogether. The oral alkylating agent temozolomide has emerged as a potential initial treatment option for LGG. A few reports suggest an association between temozolomide and reduced seizure frequency in patients with intractable epilepsy. Methods Using their clinical database, the authors identified adult patients whose LGGs were treated using temozolomide as the initial antineoplastic therapy at the University of Virginia Health System. As a control group, the authors assessed patients whose LGGs were under observation. All patients had seizure disorders that were treated with anticonvulsants. Seizure frequency in patients with intractable epilepsy was analyzed before and after treatment with temozolomide. Age at diagnosis, sex, antiepileptic drugs, pathological subtype, surgical treatment, and follow-up until progression were also assessed. Interval seizure frequency was meticulously analyzed at each neurooncology clinic visit. A meaningful difference in seizures was defined as a reduction in seizure frequency of greater than 50% per month. Results Thirty-nine patients were identified in the temozolomide cohort and 30 patients in the control cohort. The median age at diagnosis was 46 years for the former cohort and 41.5 years for the latter. The median length of follow-up was 39 months for the temozolomide group and 37 months for the control group. There was a significant difference in reduced seizure frequency between patients receiving temozolomide (59%) and those who did not receive temozolomide (13%, p < 0.001). Seven patients (18%) in the temozolomide group displayed this improvement independent of antiepileptic drug adjustment compared with no patient in the control group (p < 0.001). Conclusions The authors' data suggest that a subset of patients with LGGs experience improvement in seizure frequency during treatment with temozolomide independent of antiepileptic drug adjustment. This decrease in seizure frequency appears independent of the natural history of seizures in patients whose tumors are under observation. Consequently, seizures in patients with LGGs may be better controlled with the combination of AEDs and temozolomide.

scholarly journals Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy

Neurology ◽  
2018 ◽  
Vol 91 (2) ◽  
pp. 82-90 ◽  
Author(s):  
Andres M. Kanner ◽  
Eric Ashman ◽  
David Gloss ◽  
Cynthia Harden ◽  
Blaise Bourgeois ◽  
...  
Keyword(s):  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Extended Release ◽  
Focal Epilepsy ◽  
Immediate Release ◽  
Juvenile Myoclonic Epilepsy ◽  
Review Literature ◽  
Treatment Resistant ◽  
New Antiepileptic Drugs ◽  
Frequency Level

ObjectiveTo update the 2004 American Academy of Neurology guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs).Methods2004 criteria were used to systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.ResultsForty-two articles were included.RecommendationsThe following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month–16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6–17 years); oxcarbazepine for TRCFE (1 month–4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.

Synaptic vesicle protein 2A tumoral expression predicts levetiracetam adverse events

2019 ◽  
Vol 266 (9) ◽  
pp. 2273-2276
Author(s):  
Michele Romoli ◽  
Martina Mandarano ◽  
Marina Romozzi ◽  
Paolo Eusebi ◽  
Chiara Bedetti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Synaptic Vesicle ◽  
Synaptic Vesicle Protein ◽  
Vesicle Protein ◽  
Synaptic Vesicle Protein 2A

scholarly journals Effectiveness of clobazam as add-on therapy in children with refractory focal epilepsy

2006 ◽  
Vol 64 (3b) ◽  
pp. 705-710 ◽  
Author(s):  
Mariana Ribeiro Marcondes da Silveira ◽  
Maria Augusta Montenegro ◽  
Renata Cristina Franzon ◽  
Carlos A.M. Guerreiro ◽  
Marilisa M. Guerreiro
Keyword(s):  
Adverse Events ◽  
Antiepileptic Drugs ◽  
Seizure Frequency ◽  
Focal Epilepsy ◽  
Safety And Efficacy ◽  
Refractory Seizures ◽  
One Year

The objective of this study was to evaluate the safety and efficacy of clobazam in children with refractory focal epilepsy. We investigated 100 consecutive patients concerning etiology of epilepsy, previously used antiepileptic drugs, seizure frequency and adverse events. Clobazam was introduced as add-on therapy in patients with previous failure of at least two monotherapies. Mean age was eight years-old and 39 patients were girls. Clobazam mean dosage was 23.6 mg/day. Mean use of clobazam was 18.6 months. Twenty-two patients had adverse events. Twenty-six patients became seizure-free, 11 had an improvement of >75% and in 58 there was no modification in seizure frequency. Five patients had an increase in seizure frequency. Clobazam efficacy lasted for more than one year in 42% of the seizure-free patients. Clobazam seems to be safe and effective in the treatment of focal epilepsy in childhood and should be considered in patients with refractory seizures.

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