PMID- 28461248
OWN - NLM
STAT- MEDLINE
DCOM- 20180319
LR  - 20181113
IS  - 1095-953X (Electronic)
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 104
DP  - 2017 Aug
TI  - Simultaneous triple therapy for the treatment of status epilepticus.
PG  - 41-49
LID - S0969-9961(17)30100-6 [pii]
LID - 10.1016/j.nbd.2017.04.019 [doi]
AB  - 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 GABA(A)R 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 GABA(A)R 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 
      GABA(A)R and NMDAR trafficking can reduce the severity of SE and its long-term 
      consequences.
CI  - Published by Elsevier Inc.
FAU - Niquet, Jerome
AU  - Niquet J
AD  - Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, 
      CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles 
      Healthcare System, Los Angeles, CA, USA. Electronic address: jniquet@ucla.edu.
FAU - Baldwin, Roger
AU  - Baldwin R
AD  - Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles 
      Healthcare System, Los Angeles, CA, USA.
FAU - Norman, Keith
AU  - Norman K
AD  - Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles 
      Healthcare System, Los Angeles, CA, USA.
FAU - Suchomelova, Lucie
AU  - Suchomelova L
AD  - Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles 
      Healthcare System, Los Angeles, CA, USA.
FAU - Lumley, Lucille
AU  - Lumley L
AD  - US Army Medical Research Institute of Chemical Defense (USAMRICD), 2900 Ricketts 
      Point Rd., Aberdeen Proving Ground, MD 21010, USA.
FAU - Wasterlain, Claude G
AU  - Wasterlain CG
AD  - Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, 
      CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles 
      Healthcare System, Los Angeles, CA, USA; Brain Research Institute, David Geffen 
      School of Medicine at UCLA, Los Angeles, CA, USA.
LA  - eng
GR  - I01 BX000273/BX/BLRD VA/United States
GR  - U01 NS074926/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20170429
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Anticonvulsants)
RN  - 01MI4Q9DI3 (Pilocarpine)
RN  - 614OI1Z5WI (Valproic Acid)
RN  - 6158TKW0C5 (Phenytoin)
RN  - B4SF212641 (fosphenytoin)
RN  - R60L0SM5BC (Midazolam)
SB  - IM
MH  - Animals
MH  - Anticonvulsants/*therapeutic use
MH  - Brain Waves/drug effects
MH  - Combined Modality Therapy
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Drug Therapy, Combination/methods
MH  - Electroencephalography
MH  - Male
MH  - Maze Learning/drug effects
MH  - Midazolam/therapeutic use
MH  - Neurons/drug effects/pathology
MH  - Phenytoin/analogs & derivatives/therapeutic use
MH  - Pilocarpine/toxicity
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Status Epilepticus/*therapy
MH  - Treatment Outcome
MH  - Valproic Acid/therapeutic use
PMC - PMC5504687
MID - NIHMS874077
OTO - NOTNLM
OT  - Cholinergic seizures
OT  - Ketamine
OT  - Midazolam
OT  - Refractory status epilepticus
OT  - Valproate
COIS- Disclosure of Conflicts of Interest Jerome Niquet and Claude Wasterlain have a 
      patent pending on polytherapy of cholinergic seizures (UC Case No. 2012-172-2). 
      Other authors have no conflict of interest to disclose.
EDAT- 2017/05/04 06:00
MHDA- 2018/03/20 06:00
PMCR- 2018/08/01
CRDT- 2017/05/03 06:00
PHST- 2017/01/12 00:00 [received]
PHST- 2017/03/27 00:00 [revised]
PHST- 2017/04/27 00:00 [accepted]
PHST- 2017/05/04 06:00 [pubmed]
PHST- 2018/03/20 06:00 [medline]
PHST- 2017/05/03 06:00 [entrez]
PHST- 2018/08/01 00:00 [pmc-release]
AID - S0969-9961(17)30100-6 [pii]
AID - 10.1016/j.nbd.2017.04.019 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2017 Aug;104:41-49. doi: 10.1016/j.nbd.2017.04.019. Epub 2017 Apr 
      29.