perampanel and Chronic-Disease

Secondary generalized tonic-clonic seizures (SGTCS) are among the most severe forms of seizures, and the main risk factor for sudden unexpected death in epilepsy (SUDEP). Whether some antiepileptic drugs (AEDs) might be more efficacious than others on SGTCS in patients with drug-resistant focal epilepsy thus represents an important clinical issue for which no data are currently available.. We performed a meta-analysis of randomized controlled trials of adjunctive AED in which information on efficacy outcomes (i.e., responder rate and/or frequency per 28 days relative to baseline) were available both for all seizure types and for SGTCS. The primary analysis evaluated the efficacy of AEDs on all types of seizure and on SGTCS by comparing the responder rates for AED and for placebo.. Responder rate was available both for all seizure types and for SGTCS in 13 of the 72 eligible trials, evaluating 7 AEDs. Only three AEDs--lacosamide, perampanel and topiramate--showed greater efficacy than placebo. However, confidence intervals of relative risks overlapped for all AEDs but pregabalin, which demonstrated significantly lower efficacy than lacosamide, perampanel, and topiramate. Moreover, there was a nonsignificant trend toward a lower relative risk of responder rate for SGTCS than for all seizure types, which appeared related to a greater response to placebo for this outcome.. Indirect comparison of AEDs using randomized placebo-controlled add-on trials does not support robust differences between AEDs to prevent SGTCS. Alternative designs for evaluation of therapeutic interventions in patients at risk for SGTCS-related complications are required.

Topics: Acetamides; Anticonvulsants; Chronic Disease; Death, Sudden; Early Medical Intervention; Epilepsies, Partial; Fructose; Humans; Lacosamide; Nitriles; Pyridones; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Seizures; Topiramate; Treatment Outcome

Insomnia is the most prevalent sleep disorder in the general population, and one of the most frequent reasons for consultation in the Sleep Units. Perampanel is an antiepileptic also effective on the structure of sleep, and in restless legs syndrome. We describe the first study that evaluates perampanel in patients with chronic insomnia.. Observational retrospective cohorts study of 66 patients with chronic resistant insomnia, 33 exposed to perampanel, other 33 as non-exposed group. All patients attended in Neurology or Psychiatry Consultation, from November 2017 to November 2018. Patients included had been treated with more than 4 different drugs in the previous 4 years. We reviewed age, sex, insomnia etiology, years of evolution, number of previously used drugs, and the results of perampanel for insomnia after 3 months of treatment in the exposed cohort, measured by the improvement of 3 or more points in the ISI and Pittsburgh scales, as well as the average of hours of sleep gained. Non-exposed patients were matched with this variables, but never treated with perampanel.. We have included 66 patients. In the exposed cohort: we describe 33 patients with chronic resistant insomnia, 20 women (60 %), 13 men (40 %). Average age 53.48 years, average time of evolution: 11.25 years. Main etiology: depression 13 cases (40 %). After the combination of perampanel 2-4 mg (100 %) with antidepressants (17 cases, 51.5 %) or anxiolytics (12 cases, 36.36 %) along 3 months: the total number of hours of sleep improves in 2.5 h, the scale ISI improves by 6 points (± 2.1 SD, p = 0.02), and Pittsburgh scale improves in 4 points (± 1.7, p = 0.04). In non-exposed cohort, the improvement of the ISI scale was 2.2 points (±0.8, p = 0.06), on the Pittsburgh scale was 1.6 points (± 0.5, p = 0.01). The main adverse effect was irritability in 3 patients, without withdrawal perampanel. The treatment was abandoned by 4 patients (12.12%): 1 due to persistent irritability (3%), 2 due to lack of efficacy (6 %), 1 due to pregnancy wish (3 %).. The combination of Perampanel with an antidepressant, or an anxiolytic, improves the quality of sleep measured by ISI and Pittsburgh scales (statistically significant), probably due to its antagonistic action on glutamate. A clinical trial compared with placebo would be necessary to corroborate these results.

Topics: Adult; Anti-Anxiety Agents; Anticonvulsants; Antidepressive Agents; Anxiety Disorders; Chronic Disease; Depressive Disorder; Drug Therapy, Combination; Female; Humans; Irritable Mood; Male; Middle Aged; Nitriles; Pyridones; Sleep Initiation and Maintenance Disorders; Treatment Outcome

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.

Topics: Animals; Benzodiazepines; Chronic Disease; Down-Regulation; Epilepsy; Hippocampus; Male; Models, Biological; NF-kappa B; Nitriles; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyridones; Rats, Sprague-Dawley; Receptors, AMPA; Up-Regulation

The present study explores the pain attenuating effect of perampanel, AMPA receptor antagonist, in chronic constriction injury-induced neuropathic pain. Chronic Constriction Injury was performed by putting four loose ligatures around the sciatic nerve. Pain was assessed by determining mechanical hyperalgesia, cold allodynia and heat hyperalgesia on 7th and 14th day post surgery. Perampanel (3mg and 6mg/kg, p.o.) was administered 30min before pain assessment test on 14th day post-surgery. CCI led to significant development of pain and peak symptoms were observed on 14th day. Perampanel significantly attenuated CCI-induced mechanical hyperalgesia, cold allodynia and heat hyperalgesia, at different time intervals 30, 60, 90, 120min, with more substantial effect observed at dose of 6mg/kgNaloxone was administered in CCI subjected rats before perampanel treatment to explore the potential role of opioids in anti-nociceptive effects of perampanel. Naloxone decreased the pain attenuating effects of perampanel significantly, indicating a critical role of opioid system in anti-nociceptive potential of perampanel. Perampanel has pain attenuating potential in CCI-induced neuropathic pain, which may be due to partly mediated through the opioid system.

Topics: Animals; Chronic Disease; Constriction; Disease Models, Animal; Female; Hyperalgesia; Male; Motor Activity; Naloxone; Neuralgia; Nitriles; Pyridones; Rats, Wistar

The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy.

Topics: Animals; Anticonvulsants; Chronic Disease; Disease Models, Animal; Electroencephalography; Epilepsy, Temporal Lobe; Female; Hippocampus; Kainic Acid; Mice; Nitriles; Phenytoin; Pyridones; Quinoxalines; Receptors, AMPA; Seizures; Status Epilepticus