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 (100. mg/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 (100. mg/kg) and pentobarbital (30. mg/kg). After 4-6. h of SPD-induced suppression, EEG activity often overshot control levels at 7-12. h. Valnoctamide (VCD, 180. mg/kg), an SPD homolog, was also efficacious at 30. min. SPD blocks pilocarpine-induced electrographic seizures when administered at 1. h 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.
| Original language | English |
|---|---|
| Pages (from-to) | 145-156 |
| Number of pages | 12 |
| Journal | Neuroscience |
| Volume | 231 |
| DOIs | |
| State | Published - 2 Feb 2013 |
Bibliographical note
Funding Information:This research is supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD) , and the National Institute of Neurological Disorders and Stroke (NINDS) , Grant No. NO1-NS-4-2359 (WP, KR, BR, CN, and FED).
Funding Information:
Dr. Dudek has received financial support in the form of grants, gifts, and/or consulting fees from the Johnson Pharmaceutical Research Institute, Johnson-Ethicon, Neurotherapeutics Pharma, and the Epilepsy Therapy Project. He has also received consulting fees from and has equity interest in Epitel, Inc. Dr. Bialer has received in the last 3 years as speaker consultancy fees from Bial, CTS Chemicals, Desitin, Janssen-Cilag, Johnson & Johnson, Medgenics, Rekah, Sepracor, Teva, UCB Pharma, and Upsher-Smith. In the last 5 years, Dr. Bialer has received research grants from the Jazz Pharmaceuticals, Johnson & Johnson, and the Epilepsy Therapy Development Project. Yissum Research & Development Company of the Hebrew University of Jerusalem owns patents on racemic-SPD and its individual stereoisomers. None of the other authors have any conflicts of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Keywords
- Diazepam
- EEG
- Epilepsy
- Pilocarpine
- Seizure
- Valproic acid