title: Treatment of experimental status epilepticus with synergistic drug combinations.
abstract: During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAARs) 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 GABAARs is drastically reduced, and a GABAAagonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAARs), 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.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, U.S.A.
authors.forename: Jerome
authors.initials: J
authors.lastname: Niquet
authors.affiliation: Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, U.S.A.
authors.forename: Roger
authors.initials: R
authors.lastname: Baldwin
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, U.S.A.
authors.forename: Lucie
authors.initials: L
authors.lastname: Suchomelova
authors.affiliation: US Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, Maryland, U.S.A.
authors.forename: Lucille
authors.initials: L
authors.lastname: Lumley
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, U.S.A.
authors.forename: Roland
authors.initials: R
authors.lastname: Eavey
authors.affiliation: Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.|Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, U.S.A.|Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A.
authors.forename: Claude G
authors.initials: CG
authors.lastname: Wasterlain
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004567:Electrodes, Implanted; D004569:Electroencephalography; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D018755:GABA Agonists / Q000627:therapeutic use; D008297:Male; D018721:Muscarinic Agonists / Q000633:toxicity; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018721:Muscarinic Agonists; D010862:Pilocarpine
keywords: Cholinergic seizures; Diazepam; Ketamine; Polytherapy; Refractory status epilepticus; Valproate