Bumetanide for neonatal seizures : No light in the pharmacokinetic/dynamic tunnel

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http://hdl.handle.net/10138/346712

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Kaila , K & Löscher , W 2022 , ' Bumetanide for neonatal seizures : No light in the pharmacokinetic/dynamic tunnel ' , Epilepsia , vol. 63 , no. 7 , pp. 1868-1873 . https://doi.org/10.1111/epi.17279

Title: Bumetanide for neonatal seizures : No light in the pharmacokinetic/dynamic tunnel
Author: Kaila, Kai; Löscher, Wolfgang
Contributor organization: Molecular and Integrative Biosciences Research Programme
Neuroscience Center
Kai Kaila / Principal Investigator
Laboratory of Neurobiology
University of Helsinki
Helsinki Institute of Life Science HiLIFE
Date: 2022-07
Language: eng
Number of pages: 6
Belongs to series: Epilepsia
ISSN: 0013-9580
DOI: https://doi.org/10.1111/epi.17279
URI: http://hdl.handle.net/10138/346712
Abstract: In his editorial, Kevin Staley criticizes our recent work demonstrating the lack of effect of bumetanide in a novel model of neonatal seizures. The main points in our response are that (1) our work is on an asphyxia model, not one on "hypercarbia only"; (2) clinically relevant parenteral doses of bumetanide applied in vivo lead to concentrations in the brain parenchyma that are at least an order of magnitude lower than what would be sufficient to exert any direct effect-even a transient one-on neuronal functions, including neonatal seizures; and (3) moreover, bumetanide's molecular target in the brain is the Na-K-2Cl cotransporter NKCC1, which has vital functions in neurons, astrocytes, and oligodendrocytes as well as microglia. This would make it impossible even for highly brain-permeant NKCC1 blockers to specifically target depolarizing and excitatory actions of gamma-aminobutyric acid in principal neurons of the brain, which is postulated as the rationale of clinical trials on neonatal seizures.
Subject: animal models
bumetanide
hypoxic-ischemic encephalopathy
neonatal seizures
NKCC1
CATION-CHLORIDE COTRANSPORTERS
IMPERMEANT ANIONS ESTABLISH
CARBON-DIOXIDE
HYPOXIA
BRAIN
PHARMACOLOGY
KCC2
PATHOPHYSIOLOGY
ACCUMULATION
3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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