ArticleAnnals of neurology2008
Bumetanide enhances phenobarbital efficacy in a neonatal seizure model.
Article in Annals of neurology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00830531 (Pilot Study of Bumetanide for Newborn Seizures), which is not on this map. Cited by 122 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Pilot Study of Bumetanide for Newborn Seizures: A Phase I Study of Pharmacokinetics and Safety of Bumetanide for Neonatal Seizures
Who cites it
122 citing papers in PubMed, 1 synthesis or guideline pooled it, 268 citations in OpenAlex.
- Anti-seizure medications for neonates with seizures.The Cochrane database of systematic reviews · 2023Pooled it
- Clarifications regarding bumetanide for neonatal seizures.Epilepsia · 2022Trial
- A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.Annals of neurology · 2021Trial
- WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate.bioRxiv : the preprint server for biology · 2026Article
- Chasing the ghost in the code: highlighting the mystery of a rare genetic condition.American journal of physiology. Cell physiology · 2026Review
- Plasma KCC2, NKCC1, and GABA as peripheral biomarkers in autism spectrum disorder: a combined ROC analysis.Metabolic brain disease · 2026Article
- The First 30 Days Postnatal of the GABA Receptor: A Comprehensive Overview.Molecular neurobiology · 2025Review
- Neonatal sevoflurane exposure enhances stress-related neurological susceptibility via NKCC1 modulation.Scientific reports · 2025Article
- Age-related impact of phenobarbital in suppressing prenatal alcohol exposure-related seizures in developing rats.Alcohol (Fayetteville, N.Y.) · 2025Article
- Revolutionising Neurological Therapeutics: Investigating Drug Repurposing Strategies.CNS & neurological disorders drug targets · 2025Review
- Timing of interventions to control neuronal chloride elevation in a model of neonatal seizures after hippocampal injury.Epilepsia · 2024Article
- The role ofJournal of pharmaceutical analysis · 2023Review
- New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development.CNS drugs · 2023Review
- Molecular Mechanisms of Epilepsy: The Role of the Chloride Transporter KCC2.Journal of molecular neuroscience : MN · 2022Review
- Bumetanide Effects on Resting-State EEG in Tuberous Sclerosis Complex in Relation to Clinical Outcome: An Open-Label Study.Frontiers in neuroscience · 2022Article
- Changes in breathing pattern during severe hypothermia and autoresuscitation from hypothermic respiratory arrest in anesthetized mice.Physiological reports · 2021Article
- Don't Get BUM'd Out: Bumetanide May yet Prove Beneficial for Neonatal Seizures.Epilepsy currents · 2021Article
- Novel Therapeutics for Neonatal Seizures.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Unique Actions of GABA Arising from Cytoplasmic Chloride Microdomains.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details.Epilepsia · 2021Article
62 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
Abstract
objectivesHigh levels of expression of the Na+-K+-2Cl- (NKCC1) cotransporter in immature neurons cause the accumulation of intracellular chloride and, therefore, a depolarized Cl- equilibrium potential (E(Cl)). This results in the outward flux of Cl- through GABA(A) channels, the opposite direction compared with mature neurons, in which GABA(A) receptor activation is inhibitory because Cl- flows into the cell. This outward flow of Cl- in neonatal neurons is excitatory and contributes to a greater seizure propensity and poor electroencephalographic response to GABAergic anticonvulsants such as phenobarbital and benzodiazepines. Blocking the NKCC1 transporter with bumetanide prevents outward Cl- flux and causes a more negative GABA equilibrium potential (E(GABA)) in immature neurons. We therefore tested whether bumetanide enhances the anticonvulsant action of phenobarbital in the neonatal brain
methodsRecurrent seizures were induced in the intact hippocampal preparation in vitro by continuous 5-hour exposure to low-Mg2+ solution. The anticonvulsant efficacy of phenobarbital, bumetanide, and the combination of these drugs was studied
resultsPhenobarbital failed to abolish or depress recurrent seizures in 70% of hippocampi. In contrast, phenobarbital in combination with bumetanide abolished seizures in 70% of hippocampi and significantly reduced the frequency, duration, and power of seizures in the remaining 30%
interpretationThus, alteration of Cl- transport by bumetanide enables the anticonvulsant action of phenobarbital in immature brain. This is a mechanistic demonstration of rational anticonvulsant polypharmacy. The combination of these agents may comprise an effective therapy for early-life seizures.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.