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Title: An investigation of nerve excitability measures to detect the effect of ion channel active medications on peripheral nerve
Author: Molyneux, Adam James
ISNI:       0000 0004 8499 8444
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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This thesis details the application of nerve excitability testing to myelinated peripheral motor and sensory nerve in order to detect and describe the effects of drugs which prior knowledge tells us act as sodium channel inhibitors. The techniques used are applicable to human subjects as well as both in-vivo and ex-vivo animal preparations. The main drug of investigation is carbamazepine. Carbamazepine has been well studied and it is used here primarily to investigate the electrophysiological techniques applied and their sensitivity to its described action. Chapter 1 provides the historical background to the modern electrophysiological technique of threshold tracking and nerve excitability studies. The fundamentals of nervous transmission and sodium channels are described along with the history and known mechanisms of action for relevant sodium channel inhibiting compounds. Chapter 2 provides the rationale for employing these particular techniques to investigate the effect of sodium channel blocking drugs and states two hypotheses. In this section two further hypotheses are stated which required an evolution of the existing nerve excitability techniques in order investigate. The reasoning behind this is discussed. Chapter 3 describes the method to apply nerve excitability studies to healthy human subjects, before and after carbamazepine and rat exvivo saphenous nerve exposed to carbamazepine and its metabolite carbamazepine epoxide. An adaptation to the testing protocol, threshold tracking of repeated stimuli at different frequencies, is described with the intention of more fully elucidating the drug property of use or frequencydependence. Chapter 4 and Chapter 5 present results demonstrating that the effect of carbamazepine is detectable in both ex-vivo rat nerve and healthy human subjects with the results differing between human motor and sensory nerve. Chapter 6 extends current electrophysiological techniques with a novel protocol designed to draw out features of sodium channel inhibition not well demonstrated by the current technique, that of frequency-dependence. Lidocaine, tetrodotoxin and carbamazepine are compared in the ex-vivo preparation. Chapter 7 provides a discussion and implications of the findings. Chapter 8 presents an adjustment to the current mathematical model of human motor nerve in order to improve the ability to describe drugs which inhibit sodium channels. The results of implementing this change are then presented and discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available