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Title: Pharmacokinetics of stilbene analogues and their application as novel anti-inflammatory agents for chronic obstructive pulmonary disease
Author: Yeo, Samuel Chao Ming
ISNI:       0000 0004 7963 6852
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Chronic obstructive pulmonary disease (COPD) is an escalating global health problem that is associated with massive healthcare costs. There are currently no effective therapies which can significantly ameliorate the underlying inflammation and alter the natural history of this disease. As such, the development of novel anti-inflammatory therapy is urgently needed. Resveratrol, the stilbene analogue found naturally in berries, has anti-oxidant and anti-inflammatory effects in several disease models related to airway inflammation. However, its therapeutic application is limited by its relatively weak potency and poor pharmacokinetics and its anti-inflammatory mechanisms have not been fully elucidated. In recent years, other stilbene analogues have emerged as viable alternatives with superior pharmacokinetics and potency but their pharmacological properties are still not well understood. This project extensively investigated the pharmacology of stilbene analogues by first profiling the pharmacokinetics of some analogues to identify possible structural determinants of pharmacokinetics, followed by examining the anti-inflammatory effects and cellular mechanisms of these compounds to identify promising drug candidates. Studies in this thesis using a pre-clinical rat pharmacokinetic model indicated that meta-hydroxy groups in the stilbene analogue structure are associated with poor pharmacokinetics and methylation appears to reduce its susceptibility to clearance. Using transformed and primary airway epithelial cell models, some stilbene analogues were shown to be more potent than resveratrol in inhibiting the release of inflammatory cytokines, IL-6 and CXCL8. Their anti-inflammatory actions involved the suppression of major inflammatory transcription factors, NF-κB and AP-1, and more importantly, were mediated through abrogating the activation of the PI3K/Akt signalling pathway, which is distinct from the actions of dexamethasone. These studies established isorhapontigenin as the most potent stilbene analogue with better pharmacokinetics than resveratrol which substantiate its further development as a novel anti-inflammatory agent for COPD.
Supervisor: Donnelly, Louise E. ; Barnes, Peter J. ; Lin, Haishu Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral