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Treatment of experimental status epilepticus with synergistic drug combinations
Author(s) -
Niquet Jerome,
Baldwin Roger,
Suchomelova Lucie,
Lumley Lucille,
Eavey Roland,
Wasterlain Claude G.
Publication year - 2017
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13695
Subject(s) - pharmacology , diazepam , status epilepticus , benzodiazepine , gabaa receptor , drug , ketamine , chemistry , nmda receptor , anticonvulsant , epilepsy , receptor , medicine , anesthesia , neuroscience , psychology , biochemistry
Summary During status epilepticus ( SE ), synaptic γ‐aminobutyric acid A receptors ( GABA A R s) become internalized and inactive, whereas spare N ‐methyl‐ d ‐aspartate receptors ( NMDAR s) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABA A R s 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 R s), 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 .