1. Treatment of experimental status epilepticus with synergistic drug combinations
- Author
-
Jerome Niquet, Claude G. Wasterlain, Lucie Suchomelova, Roland Eavey, Lucille A. Lumley, and Roger A. Baldwin
- 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 - 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.
- Published
- 2017