Journal
EPILEPSIA
Volume 58, Issue 4, Pages E49-E53Publisher
WILEY
DOI: 10.1111/epi.13695
Keywords
Refractory status epilepticus; Cholinergic seizures; Polytherapy; Diazepam; Ketamine; Valproate
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Funding
- Department of Veterans Health Affairs [I01 BX000273-07]
- NINDS (NIH Counteract Program) [UO1 NS074926]
- James and Debbie Cho Foundation
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During status epilepticus (SE), synaptic -aminobutyric acid A receptors (GABA(A)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 GABA(A)Rs is drastically reduced, and a GABA(A) agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABA(A)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.
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