Phenobarbital and midazolam suppress neonatal seizures in a noninvasive rat model of birth asphyxia, whereas bumetanide is ineffective.
Animals
Animals, Newborn
Anticonvulsants
/ therapeutic use
Asphyxia Neonatorum
/ complications
Bumetanide
/ therapeutic use
Disease Models, Animal
Female
Hypnotics and Sedatives
/ therapeutic use
Male
Midazolam
/ therapeutic use
Phenobarbital
/ therapeutic use
Rats
Rats, Wistar
Seizures
/ drug therapy
Sodium Potassium Chloride Symporter Inhibitors
/ therapeutic use
Treatment Outcome
GABA
NKCC1
antiseizure drugs
neonates
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
revised:
03
11
2020
received:
07
08
2020
accepted:
05
11
2020
pubmed:
2
12
2020
medline:
22
9
2021
entrez:
1
12
2020
Statut:
ppublish
Résumé
Neonatal seizures are the most frequent type of neurological emergency in newborn infants, often being a consequence of prolonged perinatal asphyxia. Phenobarbital is currently the most widely used antiseizure drug for treatment of neonatal seizures, but fails to stop them in ~50% of cases. In a neonatal hypoxia-only model based on 11-day-old (P11) rats, the NKCC1 inhibitor bumetanide was reported to potentiate the antiseizure activity of phenobarbital, whereas it was ineffective in a human trial in neonates. The aim of this study was to evaluate the effect of clinically relevant doses of bumetanide as add-on to phenobarbital on neonatal seizures in a noninvasive model of birth asphyxia in P11 rats, designed for better translation to the human term neonate. Intermittent asphyxia was induced for 30 minutes by exposing the rat pups to three 7 + 3-minute cycles of 9% and 5% O All untreated rat pups had seizures within 10 minutes after termination of asphyxia. Phenobarbital significantly blocked seizures when applied before asphyxia at 30 mg/kg but not 15 mg/kg. Administration of phenobarbital after asphyxia was ineffective, whereas midazolam (0.3 or 1 mg/kg) exerted significant antiseizure effects when administered before or after asphyxia. In general, focal seizures were more resistant to treatment than generalized convulsive seizures. Bumetanide (0.3 mg/kg) alone or in combination with phenobarbital (15 or 30 mg/kg) exerted no significant effect on seizure occurrence. The data demonstrate that bumetanide does not increase the efficacy of phenobarbital in a model of birth asphyxia, which is consistent with the negative data of the recent human trial. The translational data obtained with the novel rat model of birth asphyxia indicate that it is a useful tool to evaluate novel treatments for neonatal seizures.
Substances chimiques
Anticonvulsants
0
Hypnotics and Sedatives
0
Sodium Potassium Chloride Symporter Inhibitors
0
Bumetanide
0Y2S3XUQ5H
Midazolam
R60L0SM5BC
Phenobarbital
YQE403BP4D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
920-934Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
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