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

Simple item page
dc.check.chapterOfThesisEntire Thesis
dc.check.date10000-01-01
dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.infoIndefiniteen
dc.check.opt-outNoen
dc.check.reasonThis thesis contains third party copyrighted materials for which permission was not given for online useen
dc.contributor.advisorCryan, John F.en
dc.contributor.advisorBoylan, Geraldine B.en
dc.contributor.advisorGriffin, Brendan T.en
dc.contributor.authorDonovan, Maria D.
dc.contributor.funderIrish Research Councilen
dc.date.accessioned2017-06-16T11:37:53Z
dc.date.issued2015
dc.date.submitted2015
dc.description.abstractSeizures 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.sponsorshipIrish Research Council (EMBARK initiative)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationDonovan, 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.endpage228en
dc.identifier.urihttps://hdl.handle.net/10468/4084
dc.languageEnglishen
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2015, Maria D. Donovan.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectBumetanideen
dc.subjectPharmacokineticsen
dc.subjectNeonatal seizuresen
dc.subjectBlood-brain barrieren
dc.subjectEfflux transporteren
dc.subjectPhysiologically-based pharmacokinetic modellingen
dc.thesis.opt-outfalse
dc.titleNovel strategies to enhance bumetanide concentrations in the brain in the treatment of neonatal seizuresen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisorbrendan.griffin@ucc.ie
Files
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
5.62 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Doctoral Theses
Anatomy and Neuroscience - Doctoral Theses
College of Medicine and Health - Doctoral Theses
Pharmacy - Doctoral Theses