Novel strategies to enhance bumetanide concentrations in the brain in the treatment of neonatal seizures

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dc.contributor.advisor Cryan, John F. en
dc.contributor.advisor Boylan, Geraldine B. en
dc.contributor.advisor Griffin, Brendan T. en Donovan, Maria D. 2017-06-16T11:37:53Z 2015 2015
dc.identifier.citation Donovan, M. D. 2015. Novel strategies to enhance bumetanide concentrations in the brain in the treatment of neonatal seizures. PhD Thesis, University College Cork. en
dc.identifier.endpage 228 en
dc.description.abstract Seizures are a prevalent neurodevelopmental disorder that affect up to 5/1000 newborns. Seizures result in detrimental developmental outcomes for many neonates, including mortality, disability and epilepsy. Current antiepileptic treatments, such as phenobarbital, display poor efficacy rates. Gamma-aminobutyric acid (GABA)-mediated signalling may promote excitatory neurotransmission in neonates with a birth injury due to intracellular accumulation of chloride. Bumetanide is a potential adjunct treatment for neonatal seizures, which reduces intracellular chloride concentrations by inhibiting the sodium-potassium-chloride cotransporter NKCC1. This accelerates the excitatory to inhibitory switch in GABA neurotransmission. In vitro bidirectional permeability assays were used to determine the apparent permeability of bumetanide and the potential for bumetanide efflux by organic anion transporter 3 (OAT3). Bumetanide was found to be a transported efflux substrate of human OAT3, thus OAT3 inhibition is a potential therapeutic augmentation strategy. OAT3 inhibition was investigated in vivo using an integrated intracerebral microdialysis model for the potential to augment bumetanide concentrations in the brain. Bumetanide was detected in brain extracellular fluid and this concentration increased after probenecid administration. An in vivo model of hypoxic-ischaemic neonatal seizures was established to quantify the pharmacodynamic effect of bumetanide in seizures. OAT3 inhibition enhanced the concentration of bumetanide in the brain in this model. Seizure burden in these animals was reduced significantly by phenobarbital and bumetanide and decreased further when an OAT3 inhibitor was administered. Physiologically-based pharmacokinetic modelling was employed to predict plasma and brain concentrations of bumetanide in a virtual neonatal population. The simulated brain tissue concentrations of bumetanide in neonates were below the half-maximal inhibitory concentration for the target transporter NKCC1. However, large interindividual variability and a paucity of physiological limited the accuracy of these simulations. In summary, augmentation strategies that focus on preventing bumetanide efflux from the brain via OAT3 may contribute to an improved outcome for neonates with seizures. en
dc.description.sponsorship Irish Research Council (EMBARK initiative) en
dc.format.mimetype application/pdf en
dc.language English en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2015, Maria D. Donovan. en
dc.rights.uri en
dc.subject Bumetanide en
dc.subject Pharmacokinetics en
dc.subject Neonatal seizures en
dc.subject Blood-brain barrier en
dc.subject Efflux transporter en
dc.subject Physiologically-based pharmacokinetic modelling en
dc.title Novel strategies to enhance bumetanide concentrations in the brain in the treatment of neonatal seizures en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text not available en Indefinite en 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder Irish Research Council en
dc.description.status Not peer reviewed en Anatomy en Pharmacy en
dc.check.reason This thesis contains third party copyrighted materials for which permission was not given for online use en
dc.check.opt-out No en
dc.thesis.opt-out false
dc.check.chapterOfThesis Entire Thesis
dc.check.embargoformat Both hard copy thesis and e-thesis en
dc.internal.conferring Summer 2016 en

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© 2015, Maria D. Donovan. Except where otherwise noted, this item's license is described as © 2015, Maria D. Donovan.
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