| Summary: | This thesis covers several areas which are related to the potential therapeutic effect of topical nicotine in ulcerative colitis (UC) and Crohn's colitis. It also examines a possible mechanism which may be pertinent to its mode of action. Transdermal nicotine is of benefit for active UC but adverse events (AEs) are frequent and limit its use. This prompted development of topical delivery systems which made direct application of nicotine to the colonic mucosa possible. Nicotine liquid enemas and delayed-release oral preparations produce lower systemic blood levels of nicotine and initial work with the enema in active DC gave encouraging results. My work commenced with a dose-ranging pharmacokinetic study of nicotine enemas to establish the maximum tolerated dose, which was subsequently used in a randomised, placebo-controlled trial which involved patients with active DC. Results for the primary endpoint - induction of clinical remission, were negative, although the enemas were welltolerated with only one withdrawal due to an AE. Plasma fibrinogen was measured in a subgroup ofpatients to assess the effects of nicotine and disease activity - there appeared to be no effect of topical nicotine on fibrinogen levels and plasma fibrinogen was not suf1iciently sensitive to be of clinic~l use as a biochemical marker of disease severity. Patients previously treated with nicotine in this depaltment had commented that urge~cy to defaecate settled quickly. To examine this, a comparative study of enema retention and preference was perfOlmed but there was no difference between nicotine and other enemas. 2 Supplied by The British Library - 'The world's knowledge' Smoking has a detrimental effect in Crohn's disease (CD) but this could be due to factors other than nicotine and related to smoking. Given the considerable overlap in the . . treatment ofUC and CD, a small pilot study of nicotine enemas for active Crohn's colitis was conducted; there was no clinical deterioration and some patients improved. A delayed-release oral formulation was given to patients with more extensiv~ colitis. There was a wide vmiation in the dose of nicotine tolerated; assessment of efficacy was limited because of the 'open' nature of the observations - but some patients appeared to benefit. The laboratory work was an extension of evidence that 0.7 nicotinic acetylcholine receptors (nAChRs) on monocytes have an impOltant anti-inflanunatory role. It is conceivable that nicotine exerts an anti-inflammatory effect through these receptors but there was no data relating to the colon. LabeIledo.-bungarotoxin was used to detect 0.7 nAChRs in human colonic mucosa. They were present on a few cells of the lamina proplia which are possibly dendritic cells (DCs) based on their morphological and phenotypic features. Future investigations might include the roles in colitis of delayed-release oral nicotine e and formulations which reproduce the phannacokinetic profile ofplasma nicotine seen in smokers. The possibility that nicotine may help us understand the pathogenesis ofcolitis and lead to therapeutic alternatives is attractive and requires further exploration.
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