Simultaneous triple therapy for the treatment of status epilepticus

Niquet, Jérôme; Baldwin, Roger A.; Norman, Keith; Suchomelova, Lucie; Lumley, Lucille A.; Wasterlain, Claude G.

doi:10.1016/j.nbd.2017.04.019

Cited by 40 publications

(62 citation statements)

References 34 publications

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“…A recent study demonstrated that perampanel terminated status epilepticus in a pilocarpine model of status epilepticus, but amantadine, an NMDA receptor antagonist, did not [163]. Similarly, the NMDA antagonist ketamine did not demonstrate a stable effect in animal models of status epilepticus when administered as monotherapy, but showed synergistic efficacy when administered in combination therapy with other drugs [165][166][167][168]. As such, AMPA antagonists appear to have an advantage over NMDA antagonists in the termination of self-sustained synchronized activity.…”

Section: Synchronized Activitymentioning

confidence: 99%

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

2020

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It is widely accepted that glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major clinical research targets. It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, perampanel, has been approved for the treatment of some forms of epilepsy. These results suggest that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety. Accumulating knowledge of both NMDA and AMPA receptors, including pathological gene mutations, roles in autoimmune epilepsy, and evidence from drug-discovery research and pharmacological studies, may provide valuable information enabling the roles of both receptors in ictogenesis to be reconsidered. This review aimed to integrate information from several studies in order to further elucidate the specific roles of NMDA and AMPA receptors in epilepsy.

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Section: Synchronized Activitymentioning

confidence: 99%

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

2020

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“…When treatment is delivered late, there may not be enough GABA A Rs left in synapses to fully restore inhibition, and an additional AED which enhances inhibition at a nonbenzodiazepine site provides additional benefit [15]. The choice of the best AED for that purpose would require too much space for this brief review.…”

Section: Choice Of Drugsmentioning

confidence: 99%

“…The results support the receptor trafficking hypothesis. Methods have been published [14,15] and will not be described in this brief review.…”

mentioning

confidence: 99%

Early polytherapy for benzodiazepine-refractory status epilepticus

Niquet

Lumley²,

Baldwin

et al. 2019

Epilepsy & Behavior

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The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABA A) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABA A receptors (GABA A R), using an allosteric GABA A R modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABA A R allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSEassociated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABA A R and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which ch...

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“…In cholinergic stimulation models of SE, NMDA receptor antagonists alone are ineffective in terminating benzodiazepine‐refractory SE. However, when these drugs are combined with benzodiazepines, they work synergistically to end seizures …”

Section: Role Of Nmda Receptors In Sementioning

confidence: 99%

“…However, when these drugs are combined with benzodiazepines, they work synergistically to end seizures. [15][16][17] SE results in neuronal injury and death. Both necrotic and programmed cell death are reported to occur as a result of SE.…”

Section: Role Of Nmda Receptors In Sementioning

confidence: 99%

Role of NMDA receptors in the pathophysiology and treatment of status epilepticus

Kapur

2018

Epilepsia Open

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SummaryThis review considers the role of N‐methyl‐d‐aspartate receptors in the pathophysiology and treatment of status epilepticus (SE). NMDA receptors play a critical role in sustaining SE by mediating the plasticity of γ‐aminobutyric acid (GABA)‐A and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors, neuronal loss, and epileptogenesis. In parallel, there is growing interest in using the NMDA receptor antagonist ketamine in the treatment of refractory SE. Ketamine has proved to be safe for use in refractory and super‐refractory SE in patients. The pilot studies also suggest that ketamine may be efficacious for termination of refractory SE.

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Simultaneous triple therapy for the treatment of status epilepticus

Cited by 40 publications

References 34 publications

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

Early polytherapy for benzodiazepine-refractory status epilepticus

Role of NMDA receptors in the pathophysiology and treatment of status epilepticus

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