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Towards local delivery of therapeutics for the treatment of eosinophilic oesophagitis

Taherali, Farhan Kayyum; (2021) Towards local delivery of therapeutics for the treatment of eosinophilic oesophagitis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Eosinophilic oesophagitis (EoE) is a chronic inflammatory disease of the oesophagus leading to lifelong morbidity. EoE has an increasing prevalence with the current mainstay of therapy being oral corticosteroid, budesonide, intended for topical action. This contribution examines the potential for local application of tacrolimus and monoclonal antibody (mAb), infliximab to the oesophagus. Tacrolimus, is used topically for atopic dermatitis and has shown to ameliorate, IL-5 and IL-13 in a mouse model of EoE whereas mAbs are administered parenterally for treating EoE. Local application of tacrolimus and mAbs to the oesophagus, would serve as options for non-responder EoE patients or those suffering from side effects of steroids. Ussing permeation system was used to develop an ex-vivo injury model to mimick the histopathology of EoE; dilated intercellular spaces. Porcine oesophageal tissue (surrogate for human) was exposed to biorelevant gastroduodenorefluxate elements, until the drop in transepithelial electrical resistance (TEER) was irreversible, indicating opening of tight junctions. Tissue and basolateral accumulation after 30 minutes, was quantified using liquid chromatography tandem mass spectrometry (LCMS/MS) for budesonide and tacrolimus and ELISA for infliximab. A significant increase (p<0.05) in tissue accumulation of tacrolimus (approx. 2-fold) and infliximab (approx. 7-fold) was observed in the injured tissue versus control but no significant difference (p>0.05) was observed for budesonide. This led to the hypothesis that the efficacy of budesonide formulations may be owing to a systemic rather than local effect. However, the poor perfusion of the oesophagus challenged this hypothesis. Tail vein budesonide injection into the Sprague Dawley rat (similar oesophageal perfusion to human) showed that budesonide accumulated in the oesophagus. It is likely that currently available formulations of budesonide are absorbed and acting systemically. Molecules like tacrolimus and mAbs owing to their greater tissue accumulation in an injured epithelium, are better suited towards site specific local delivery to the oesophagus while avoiding systemic side effects.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Towards local delivery of therapeutics for the treatment of eosinophilic oesophagitis
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
URI: https://discovery.ucl.ac.uk/id/eprint/10125402
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