title: A comparative electrographic analysis of the effect of sec-butyl-propylacetamide on pharmacoresistant status epilepticus.
abstract: Better treatment of status epilepticus (SE), which typically becomes refractory after about 30 min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electroencephalograms (EEGs) were recorded from rats during ESE induced with lithium-pilocarpine. Using a previously-published algorithm, the effects of SPD on ESE were compared quantitatively to other relevant compounds. To confirm benzodiazepine resistance, diazepam (DZP) was shown to suppress ESE when administered 15 min after the first motor seizure, but not after 30 min (100mg/kg). VPA (300 mg/kg) also lacked efficacy at 30 min. SPD (130 mg/kg) strongly suppressed ESE at 30 min, less after 45 min, and not at 60 min. At a higher dose (180 mg/kg), SPD profoundly suppressed ESE at 60 min, similar to propofol (100mg/kg) and pentobarbital (30 mg/kg). After 4-6h of SPD-induced suppression, EEG activity often overshot control levels at 7-12h. Valnoctamide (VCD, 180 mg/kg), an SPD homolog, was also efficacious at 30 min. SPD blocks pilocarpine-induced electrographic seizures when administered at 1h after the first motor seizure. SPD has a faster onset and greater efficacy than DZP and VPA, and is similar to propofol and pentobarbital. SPD and structurally similar compounds may be useful for the treatment of refractory ESE. Further development and use of automated analyses of ESE may facilitate drug discovery for refractory SE.
authors.affiliation: Department of Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: W
authors.initials: W
authors.lastname: Pouliot
authors.forename: M
authors.initials: M
authors.lastname: Bialer
authors.forename: N
authors.initials: N
authors.lastname: Hen
authors.forename: T
authors.initials: T
authors.lastname: Shekh-Ahmad
authors.forename: D
authors.initials: D
authors.lastname: Kaufmann
authors.forename: B
authors.initials: B
authors.lastname: Yagen
authors.forename: K
authors.initials: K
authors.lastname: Ricks
authors.forename: B
authors.initials: B
authors.lastname: Roach
authors.forename: C
authors.initials: C
authors.lastname: Nelson
authors.forename: F E
authors.initials: FE
authors.lastname: Dudek
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology / Q000627:therapeutic use; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000577:Amides; D000927:Anticonvulsants; C570212:sec-butyl-propylacetamide; D010862:Pilocarpine; C045179:valnoctamide; D014635:Valproic Acid; D010424:Pentobarbital; D003975:Diazepam