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Maitra, Rudra Krishna (2017) Evolving new drug treatments for faecal incontinence. DM thesis, University of Nottingham.

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Abstract

Faecal incontinence is an embarrassing and socially debilitating condition which is primarily acquired and increases in prevalence with age. Current conservative measures are aimed at dietary modification and changing the consistency of stool with no targeted treatments available to address the underlying cause of incontinence. Surgical treatments are either unsatisfactory or carry significant morbidity.

There is currently increasing interest in the use of α adrenoceptor agonists to increase the tone of the anus and thereby improve continence. One of the potential drugs, L-erythro-methoxamine, has been shown to increase mean anal resting tone in healthy volunteers and is well tolerated as suppositories.

Extensive data exists on the neuromyogenic properties of the human internal anal sphincter (IAS) and its response to various drugs, particularly α adrenoceptor agonists. Little data exists on the response of the rectum to α agonists. The ideal drug treatment for incontinence would cause a contraction in the IAS and a relaxation in the rectum – increasing the reservoir of stool while augmenting the sphincter to aid continence.

We performed in vitro experiments on sheep internal anal sphincter (IAS) using an organ bath method and subjected the tissues to electrical field stimulation to mimic nerve stimulation. Our results were comparable to results of previous authors who also examined the sheep IAS. Using this validated protocol, we investigated the sheep rectum to identify the neuronal mediators of the EFS response and to investigate the effect of α1 adrenoceptor agonists. Our results showed that sheep rectum relaxes in response to nerve stimulation and this relaxation is the result of the release of nitric oxide. Contraction in response to nerve stimulation is primarily mediated by acetylcholine acting on muscarinic receptors. Methoxamine caused a contraction in the sheep rectum.

We also examined the pig IAS and rectum in vitro. An identical organ bath technique was used with Electrical Field Stimulation to mimic nerve stimulation. For both IAS and rectum in the pig, nerve stimulation caused a relaxation via nitric oxide and a contraction mediated primarily by noradrenaline acting on α1 adrenoceptors with a small component mediated by acetylcholine acting via muscarinic receptors. Methoxamine caused a contraction in both IAS and rectal tissue with similar potency in each.

We were part of an industry-sponsored multi-centre randomised placebo-controlled clinical trial investigating the safety and efficacy of L-erythro-methoxamine on patients with faecal incontinence. The nine patients recruited from our centre showed no significant improvement in the number of episodes of incontinence or in the questionnaire scores measuring the impact of incontinence on quality of life after eight weeks of daily suppositories. The drug was well tolerated with few adverse events. There were no significant safety concerns although there was a prolongation of the PR interval in post-treatment ECGs and a positive correlation between the QT intervals on ECGs with serum concentrations of the drug. Our results were typical of those obtained in the other centres. The overall result of the trial was that there was no improvement in episodes of faecal incontinence following treatment with L-erythro-methoxamine at the chosen doses.

The results from our in vitro experiments suggest that α adrenoceptor agonists may not be the best methods of treating faecal incontinence. The results from the clinical study support this finding. We believe that more in vitro studies need to be performed on human rectal tissue to confirm our findings that α adrenoceptor agonists cause a contraction in the rectum.

Item Type:	Thesis (University of Nottingham only) (DM)
Supervisors:	Maxwell-Armstrong, Charles Wilson, V.G. Scholefield, J.H.
Keywords:	Faecal incontinence
Subjects:	W Medicine and related subjects (NLM Classification) > WI Digestive system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	44517
Depositing User:	Maitra, Rudra
Date Deposited:	15 Dec 2017 04:40
Last Modified:	16 Dec 2017 02:10
URI:	https://eprints.nottingham.ac.uk/id/eprint/44517

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