PMID- 37977809
OWN - NLM
STAT- MEDLINE
DCOM- 20240119
LR  - 20240313
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 388
IP  - 2
DP  - 2024 Jan 17
TI  - Efficacy of Lacosamide and Rufinamide as Adjuncts to Midazolam-Ketamine Treatment 
      Against Cholinergic-Induced Status Epilepticus in Rats.
PG  - 347-357
LID - 10.1124/jpet.123.001789 [doi]
AB  - Benzodiazepine pharmacoresistance develops when treatment of status epilepticus 
      (SE) is delayed. This response may result from gamma-aminobutyric acid A 
      receptors (GABA(A)R) internalization that follows prolonged SE; this receptor 
      trafficking results in fewer GABA(A)R in the synapse to restore inhibition. 
      Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent 
      models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts 
      on the slow inactivation of voltage-gated sodium channels. Another ASM, 
      rufinamide, similarly acts on sodium channels by extending the duration of time 
      spent in the inactivation stage. Combination therapy of the benzodiazepine 
      midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was 
      investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult 
      male rats implanted with telemetry transmitters for monitoring 
      electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of 
      GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with 
      midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. 
      Rats were monitored continuously for seizure activity for two weeks, after which 
      brains were processed for assessment of neurodegeneration, neuronal loss, and 
      neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, 
      and lacosamide (or rufinamide) was more protective against GD-induced SE compared 
      with midazolam monotherapy. In general, lacosamide triple therapy had more 
      positive outcomes on measures of epileptogenesis, EEG power integral, and the 
      number of brain regions protected from neuropathology compared with rats treated 
      with rufinamide triple therapy. Overall, both drugs were well tolerated in these 
      combination models. SIGNIFICANCE STATEMENT: We currently report on improved 
      efficacy of antiseizure medications lacosamide and rufinamide, each administered 
      in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), 
      in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology 
      over that provided by midazolam monotherapy, or dual therapy of midazolam and 
      lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to 
      midazolam and ketamine was particularly effective against GD-induced toxicity. 
      However, protection was incomplete, suggesting the need for further study.
CI  - U.S. Government work not protected by U.S. copyright.
FAU - Lumley, Lucille A
AU  - Lumley LA
AUID- ORCID: 0000-0003-4162-8817
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.) lucille.a.lange.civ@health.mill.
FAU - Nguyen, Donna A
AU  - Nguyen DA
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.).
FAU - de Araujo Furtado, Marcio
AU  - de Araujo Furtado M
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.).
FAU - Niquet, Jerome
AU  - Niquet J
AUID- ORCID: 0000-0002-1005-0517
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.).
FAU - Linz, Emily O
AU  - Linz EO
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.).
FAU - Schultz, Caroline R
AU  - Schultz CR
AUID- ORCID: 0000-0002-3194-5993
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.).
FAU - Stone, Michael F
AU  - Stone MF
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.).
FAU - Wasterlain, Claude G
AU  - Wasterlain CG
AUID- ORCID: 0000-0002-2100-9114
AD  - Neuroscience Department, U.S. Army Medical Research Institute of Chemical 
      Defense, Aberdeen Proving Ground, Maryland (L.A.L., D.A.N., E.O.L., C.R.S., 
      M.F.S.); BioSEaD, LLC, Rockville, Maryland (M.d.A.F.); and Department of 
      Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, and 
      Epilepsy Research Laboratory, Veterans Affairs Greater Los Angeles Healthcare 
      System, Los Angeles, California (J.N., C.G.W.).
LA  - eng
GR  - U01 NS074926/NS/NINDS NIH HHS/United States
GR  - AOD21005001/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20240117
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - R60L0SM5BC (Midazolam)
RN  - 563KS2PQY5 (Lacosamide)
RN  - 690G0D6V8H (Ketamine)
RN  - WFW942PR79 (rufinamide)
RN  - 96-64-0 (Soman)
RN  - 0 (Anticonvulsants)
RN  - 12794-10-4 (Benzodiazepines)
RN  - 0 (Cholinergic Agents)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - 0 (Triazoles)
SB  - IM
MH  - Rats
MH  - Male
MH  - Animals
MH  - Midazolam/therapeutic use/pharmacology
MH  - Lacosamide/adverse effects
MH  - *Ketamine/pharmacology/therapeutic use
MH  - *Soman
MH  - Anticonvulsants/pharmacology/therapeutic use
MH  - *Status Epilepticus/chemically induced/drug therapy
MH  - Seizures/drug therapy
MH  - Benzodiazepines
MH  - Cholinergic Agents/adverse effects
MH  - gamma-Aminobutyric Acid
MH  - *Triazoles
PMC - PMC10801783
EDAT- 2023/11/18 11:42
MHDA- 2024/01/19 06:42
PMCR- 2024/02/01
CRDT- 2023/11/17 21:04
PHST- 2023/02/28 00:00 [received]
PHST- 2023/10/31 00:00 [accepted]
PHST- 2024/01/19 06:42 [medline]
PHST- 2023/11/18 11:42 [pubmed]
PHST- 2023/11/17 21:04 [entrez]
PHST- 2024/02/01 00:00 [pmc-release]
AID - jpet.123.001789 [pii]
AID - JPET_AR2023001789 [pii]
AID - 10.1124/jpet.123.001789 [doi]
PST - epublish
SO  - J Pharmacol Exp Ther. 2024 Jan 17;388(2):347-357. doi: 10.1124/jpet.123.001789.