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Garsed, Klara C. (2014) Predicting the response to Ondansetron, a 5HT3 receptor antagonist, in irritable bowel syndrome with diarrhoea: the utility of clinical features and objective biomarkers. PhD thesis, University of Nottingham.

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Abstract

Background: Patients with diarrhoea predominant irritable bowel syndrome (IBS-D) suffer from loose frequent stools with associated urgency and fear of incontinence. Relief from these symptoms is an important unmet need. The 5-HT3 receptor antagonist Alosetron has been shown to increase stool consistency, decrease urgency and reduce abdominal pain leading to a global increase in satisfaction with treatment [1]. Its use is restricted following an increased incidence of ischaemic colitis and this agent is not available in Europe.

The serine proteases family of proteolytic enzymes have been identified as the source of increased faecal proteolytic activity in patients with IBS. These enzymes may be mechanistically important via their action on the Protease activated receptor (PAR) -2, inducing increases in permeability and hypersensitivity.

Aims: To assess the efficacy of the commonly prescribed 5-HT3 antagonist Ondansetron, in patients with IBS-D and to identify biomarkers that might allow us to predict response defining an Ondansetron responsive endophenotype of IBS.

To structurally characterise faecal serine proteases and define the impact of treatment with Ondansetron.

Methods: 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo controlled, cross-over study of 5 weeks of Ondansetron 4mg versus placebo with dose titration allowed up to two tablets thrice daily in the first 3 weeks. Patients completed daily bowel symptom diaries documenting stool consistency using the Bristol Stool Form Score (BSFS). Gut transit and small bowel water content were measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment.

Faecal samples were obtained from 30 healthy volunteers (HV) and 79 IBS-D patients participating in a trial of Ondansetron versus placebo. Colonic transit was measured using radio-opaque markers. Faecal serine proteases (FSP) were purified from faecal extracts using Benzamidine-Sepharose affinity chromatography. SDS-PAGE profiled components were identified using trypsinolysis and tandem-mass-spectrometry. Functional protease activity in faecal extracts was measured using a colourimetric assay based upon the proteolysis of azo-casein.

Results: Ondansetron significantly improved stool consistency In the intention to treat analysis n= 101, with a 1.39 (95% CI1.20-1.58)point decrease on the Bristol stool form scale whilst taking Ondansetron compared to a 0.51 (95% CI 0.32-0.72) point reduction whilst taking placebo p=<0.0001. Compared to placebo patients on Ondansetron experienced fewer days with urgency (p=0.01), lower urgency scores (P<0.001), reduced frequency of defecation (p=0.001) and less bloating (p=0. 25) although pain scores did not change significantly.

Protein analysis identified the most abundant FSPs as being of human origin and likely pancreatic juice derived. Functional assays showed increased FSP and faecal amylase in IBS-D compared to HV. Those with higher amylase had significantly higher FSP and greater anxiety. FSP activity correlated negatively with whole gut transit in IBS-D (Spearman r=-0.32, p=0.005) and HV (r=-0.55, p=0.014), but was not affected by treatment with Ondansetron.

Conclusions: Ondansetron is an effective and well tolerated treatment in patients with IBS-D with a low number of side effects. It slows whole gut transit, but without a demonstrable difference in small bowel water content. Clinical rather than biochemical indicators predicted responsiveness to Ondansetron best. Patients with less severe symptoms are more likely to respond well to Ondansetron which should prove a useful addition to the current rather limited therapies available for this important group of patients.

Previous reports that FSP activity is elevated in some patients with IBS-D has been confirmed. We have increased our understanding of this phenomenon by characterising the proteins responsible for the serine protease activity, showing that most of this activity is likely due to human pancreatic enzymes.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Spiller, R.C. Marciani, L.
Keywords:	Drug treatment for irritable bowel syndrome, Biomarkers, Faecal serine proteases
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:	14332
Depositing User:	EP, Services
Date Deposited:	24 Dec 2014 09:38
Last Modified:	15 Dec 2017 10:15
URI:	https://eprints.nottingham.ac.uk/id/eprint/14332

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