A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation.
OBJECTIVE
New treatments are needed for status epilepticus (SE) that is refractory to drugs modulating GABA(A) receptors, and NMDA receptor antagonists are candidate drugs.


METHODS
Clinically available NMDA receptor antagonist ketamine was tested for effectiveness in terminating prolonged SE induced by a combination of lithium and pilocarpine. Animals were treated 10 min after first grade 5 behavioral seizure (Racine scoring scale) by intraperitoneal administration of ketamine, diazepam, or saline. Seizure termination was determined by electroencephalogram (EEG) recordings from the hippocampus and the cortex.


RESULTS
Animals treated with normal saline or either 20 mg/kg diazepam, or 50 mg/kg ketamine continued in SE for the next 300 min. However, combined treatment with diazepam and ketamine rapidly terminated prolonged cholinergic stimulation-induced SE. Detailed study of dose response relationships demonstrated that diazepam enhanced efficacy and potency of ketamine in terminating SE.


CONCLUSIONS
This study demonstrated synergistic action of diazepam and ketamine in terminating SE. It suggests that a ketamine-diazepam combination might be a clinically useful therapeutic option for the treatment of refractory SE.
Martin
Brandon S
BS
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-800394, U.S.A.
Kapur
Jaideep
J
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003975:Diazepam / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000706:statistics & numerical data; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D018020:Lithium Compounds; D008297:Male; D018721:Muscarinic Agonists; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D018020:Lithium Compounds; D018721:Muscarinic Agonists; D010862:Pilocarpine; D007649:Ketamine; D003975:Diazepam