title: Single dose efficacy evaluation of two partial benzodiazepine receptor agonists in photosensitive epilepsy patients: A placebo-controlled pilot study.
abstract: Benzodiazepines (BZDs) are highly effective to suppress various types of seizures; however, their clinical use is limited due to adverse effects and tolerance and dependence liability. Drugs that act only as partial agonists at the BZD recognition site (initially termed "BZD receptor") of the GABAA receptor chloride ionophore complex or exhibit a GABAA receptor subtype-selectivity are thought to have advantages vs. full agonists such as diazepam and most other clinically used BZDs in that such compounds have less adverse effects and reduced or absent tolerance and dependence liability. One of such compounds, abecarnil, has been clinically evaluated as a novel anxiolytic drug, but, despite its potent preclinical anti-seizure activity, it has not yet been evaluated in patients with epilepsy. In the present proof-of-concept study, we performed a within-subject placebo-controlled, single oral dose study of abecarnil in patients with photosensitive epilepsy. Flumazenil, which is generally considered a BZD receptor antagonist, but has slight partial agonistic properties, was used for comparison. In total, 12 patients were enrolled in this study. Abecarnil, 5 or 10mg, completely abolished the photo-paroxysmal EEG response, while flumazenil, 30, 60 or 100mg, was less effective. The anti-epileptic effect of abecarnil was significantly different from both placebo and flumazenil. Sedative adverse effects were observed after abecarnil but not flumazenil. The study substantiates previous pre-clinical experiments that abecarnil exerts pronounced anti-seizure activity. Epilepsy is often associated with anxiety, so that the anxiolytic activity of abecarnil would be an added advantage when using this compound in epilepsy patients.
authors.affiliation: Faculty of Medicine and Psychology, Sapienza University, Rome, Italy; Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Dorothée G A
authors.initials: DG
authors.lastname: Kasteleijn-Nolst Trenité
authors.affiliation: Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Rolf H H
authors.initials: RH
authors.lastname: Groenwold
authors.affiliation: Neurology Clinic, Wittnau, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmidt
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany. Electronic address: wolfgang.loescher@tiho-hannover.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002243:Carbolines / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D020195:Epilepsy, Reflex / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D005442:Flumazenil / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D058785:GABA-A Receptor Agonists / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D010775:Photic Stimulation / Q000009:adverse effects; D010865:Pilot Projects; D011963:Receptors, GABA-A / Q000378:metabolism; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002243:Carbolines; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D005442:Flumazenil; C062769:abecarnil
keywords: Abecarnil; Anxiety; Beta-carboline; EEG; Flumazenil; GABA; Photosensitivity