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Treatment of experimental status epilepticus with synergistic drug combinations
- Source :
- Epilepsia. 58:e49-e53
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
Abstract
- During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAA Rs) become internalized and inactive, whereas spare N-methyl-d-aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABAA Rs is drastically reduced, and a GABAA agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAA Rs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE. High doses of diazepam failed to stop electrographic SE, showing that benzodiazepine pharmacoresistance had developed. The diazepam-ketamine-valproate combination was far more effective in stopping SE than triple-dose monotherapy using the same individual drugs. Isobolograms showed that this drug combination's therapeutic actions were synergistic, with positive cooperativity between drugs, whereas drug toxicity was simply additive, without positive or negative cooperativity. As a result, the therapeutic index was improved by this drug combination compared to monotherapy. These results suggest that synergistic drug combinations that target receptor changes can control benzodiazepine-refractory SE.
- Subjects :
- Male
0301 basic medicine
Agonist
medicine.drug_class
Nonbenzodiazepine
Status epilepticus
Muscarinic Agonists
Pharmacology
Article
03 medical and health sciences
Status Epilepticus
0302 clinical medicine
Therapeutic index
Animals
Medicine
Rats, Wistar
GABA Agonists
Benzodiazepine
Dose-Response Relationship, Drug
business.industry
GABAA receptor
Pilocarpine
Drug Synergism
Electroencephalography
Electrodes, Implanted
Rats
Disease Models, Animal
030104 developmental biology
nervous system
Neurology
NMDA receptor
Anticonvulsants
Drug Therapy, Combination
Neurology (clinical)
medicine.symptom
business
Excitatory Amino Acid Antagonists
Diazepam
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 00139580
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Epilepsia
- Accession number :
- edsair.doi.dedup.....534041c786fe30172e5be1f57b10f1cd