مورد إلكتروني
Rational polytherapy in the treatment of cholinergic seizures.
| العنوان: | Rational polytherapy in the treatment of cholinergic seizures. |
|---|---|
| المؤلفون: | Niquet, Jerome |
| بيانات النشر: | eScholarship, University of California 2020-01-01 |
| تفاصيل مُضافة: | Niquet, Jerome Lumley, Lucille Baldwin, Roger Rossetti, Franco Suchomelova, Lucie Naylor, David Estrada, Ireri Betsabe Franco Schultz, Mark Furtado, Marcio de Araujo Wasterlain, Claude G |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAAR left to be able to restore inhibition with maximal GABAAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical pract |
| مصطلحات الفهرس: | Animals, Rats, Sprague-Dawley, Status Epilepticus, Valproic Acid, Ketamine, Soman, Pilocarpine, Midazolam, Muscarinic Agonists, Cholinesterase Inhibitors, Anticonvulsants, Drug Therapy, Combination, Male, Nerve Agents, Neurosciences, Brain Disorders, Epilepsy, Neurodegenerative, 6.1 Pharmaceuticals, Clinical Sciences, Neurology & Neurosurgery, publication |
| URL: | |
| الإتاحة: | Open access content. Open access content public |
| ملاحظة: | application/pdf |
| أرقام أخرى: | CDLER oai:escholarship.org:ark:/13030/qt9qj4492p qt9qj4492p https://escholarship.org/uc/item/9qj4492pTest https://escholarship.orgTest/ 1287347702 |
| المصدر المساهم: | UC MASS DIGITIZATION From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1287347702 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |