Simultaneous triple therapy for the treatment of status epilepticus

NEUROBIOLOGY OF DISEASE

卷:104

Article

Niquet, Jerome^1,2  Baldwin, Roger²  Norman, Keith²  Suchomelova, Lucie²  Lumley, Lucille³  Wasterlain, Claude G.^1,2,4 

[1] UCLA, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[2] Vet Affairs Greater Los Angeles Healthcare Syst, Epilepsy Res Lab 151, Los Angeles, CA USA

[3] USAMRICD, 2900 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010 USA

[4] UCLA, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90095 USA

关键词: Refractory status epilepticus;    Cholinergic seizures;    Midazolam;    Ketamine;    Valproate;   

DOI  :  10.1016/j.nbd.2017.04.019

来源: Elsevier

【 摘 要 】

Early maladaptive internalization of synaptic GABA(A) receptors (GABA(A)R) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences. Published by Elsevier Inc.

【 授权许可】

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