Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Motilin, normally present in a specific cell type in the upper small intestine, is believed to have a physiologic role in initiating the interdigestive migrating motor complex. Motilin may play a pathophysiologic role in the diarrhea in the irritable bowel syndrome, the dumping syndrome, chronic liver disease, and chronic renal failure. Furthermore, increased frequency of bowel movements is an important symptom in patients with the carcinoid syndrome. We have studied 73 patients with metastatic carcinoid tumors with regard to stool frequency and plasma concentration of motilin and neuropeptide K (NPK) and diurnal urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). Thirty-eight (52%) of the 73 patients had elevated (greater than 126 pmol/l) plasma concentrations of motilin, whereas 59 (81%) of the patients had diarrhea. The increased frequency of bowel motions correlated significantly (p less than 0.01) with the plasma concentrations of motilin, whereas no significant correlation with 5-HIAA and NPK was found. High-performance liquid chromatography of plasma extracts showed a single component eluting in the position of synthetic porcine motilin. However, extracts from five carcinoid tumors did not contain any significant levels of motilin. Carcinoid tumors are known to contain and secrete several biologically active substances such as serotonin, histamine, prostaglandins, and tachykinins, which are likely to cause disturbances of intestinal secretion and motility, which in turn might release motilin from the motilin-containing cells of the small intestine. The increased motilin levels might then participate in a vicious diarrhea circle together with the other agents.
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PMID:Motilin in plasma and tumor tissues from patients with the carcinoid syndrome. Possible involvement in the increased frequency of bowel movements. 244 32

The use of ondansetron, a selective serotonin 5-HT3 receptor antagonist, is well established in patients with nausea and vomiting associated with cancer chemotherapy, radiotherapy or anaesthesia and surgery. The wide distribution of 5-HT3 receptors in the body and the role of these receptors in disease have provided the rationale for investigation of ondansetron in novel applications. Preliminary data have shown ondansetron to have clinical benefit in patients with nausea and vomiting associated with drug overdosage or poisoning, anti-infective or antidepressant therapies, uraemia or neurological trauma, and in patients with pruritus. Patients with gastrointestinal motility disorders (e.g. carcinoid syndrome, irritable bowel syndrome, diarrhoea associated with cryptosporidiosis or diabetes, and chronic refractory diarrhoea) have also shown some improvement when treated with ondansetron, as have patients with certain pain or CNS-related disorders [e.g. alcohol (ethanol) dependence, opiate withdrawal, vertigo, cerebellar tremor and Parkinson's disease treatment-related psychosis]. In contrast to conventional antiemetics, ondansetron is generally well tolerated with a lower incidence of sedation and only isolated case reports of extrapyramidal reactions. Furthermore, unlike dopamine receptor-blocking neuroleptics, ondansetron does not appear to worsen the symptoms of Parkinson's disease. Thus, in addition to its established indications, preliminary results suggest that ondansetron may be beneficial in a number of novel applications. This drug may represent a treatment alternative in patients with refractory disease, or an effective treatment of conditions for which current therapies are either poorly tolerated or not available. Further investigation of ondansetron in a range of potential new applications appears to be warranted.
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PMID:Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications. 911 22

In the gut, 5-HT acts as a paracrine signalling molecule released by enterochromaffin cells and as a transmitter released by some descending serotonergic interneurons. It has a prominent role in the regulation of motility, vascular tone, secretion and perception both in normal and under certain pathophysiological conditions, such as the carcinoid syndrome and the irritable bowel syndrome (IBS). Serotonin is known to markedly influence bowel function by activating at least five receptor types (5-HT(1,2,3,4,7)). Among all 5-HT receptors, those belonging to the 5-HT3 (a ionotropic receptor) and 5-HT4 (a metabotropic receptor) type are the most extensively studied in gastroenterology, resulting in commercially available (although not worldwide) serotonergic agents for the treatment of IBS and functional dyspepsia. Recently, 5-HT7 receptors have been found to participate in the accommodation process of the circular muscle during the preparatory phase of ileal peristalsis. Since an exaggerated accommodation of the gut wall may contribute to abdominal distension and bloating, 5-HT7 receptor ligands may offer innovative opportunities for the pharmacological treatment of functional bowel disorders.
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PMID:[Recent insights into the pathogenesis of abdominal symptoms in functional bowel disorders]. 1743 64

Serotonin (5-hydroxytryptamine, 5-HT) is present in abundance within the gut, most stored in enterochromaffin cell granules. It is released by a range of stimuli, most potently by mucosal stroking. Released 5-HT stimulates local enteric nervous reflexes to initiate secretion and propulsive motility. It also acts on vagal afferents altering motility and in large amounts induces nausea. Rapid reuptake by a specific transporter (serotonin transporter, SERT) limits its diffusion and actions. Abnormally increased 5-HT is found in a range of gastrointestinal disorders including chemotherapy-induced nausea and vomiting, carcinoid syndrome, coeliac disease, inflammatory bowel disease and irritable bowel syndrome (IBS) with diarrhoea (IBS-D), especially that developing following enteric infection. Impaired SERT has been described in IBS-D and might account for some of the increase in mucosal 5-HT availability. 5-HT(3) receptor antagonists inhibit chemotherapy-induced nausea and diarrhoea associated with both carcinoid syndrome and IBS. While IBS-D is associated with increased 5-HT postprandially, IBS with constipation (IBS-C) is associated with impaired 5-HT response and responds to 5-HT(4) agonists such as Prucalopride and 5-HT(4) partial agonists such as Tegaserod.
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PMID:Recent advances in understanding the role of serotonin in gastrointestinal motility in functional bowel disorders: alterations in 5-HT signalling and metabolism in human disease. 1762 85

Beside its role as a neurotransmitter in the central nervous system, serotonin appears to be a central physiologic mediator of many gastrointestinal (GI) functions and a mediator of the brain-gut connection. By acting directly and via modulation of the enteric nervous system, serotonin has numerous effects on the GI tract. The main gut disturbances in which serotonin is involved are acute chemotherapy-induced nausea and vomiting, carcinoid syndrome and irritable bowel syndrome. Serotonin also has mitogenic properties. Platelet-derived serotonin is involved in liver regeneration after partial hepatectomy. In diseased liver, serotonin may play a crucial role in the progression of hepatic fibrosis and the pathogenesis of steatohepatitis. Better understanding of the role of the serotonin receptor subtypes and serotonin mechanisms of action in the liver and gut may open new therapeutic strategies in hepato-gastrointestinal diseases.
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PMID:Role of serotonin in the hepato-gastroIntestinal tract: an old molecule for new perspectives. 1808 89

A 36-year-old male who carried a diagnosis of irritable bowel syndrome presented with chronic watery diarrhea and was found to have hepatomegaly on physical exam. A computed tomography (CT) scan of the abdomen revealed hepatomegaly with lesions suspicious for metastatic disease. A colonoscopy revealed a polypoid lesion in the terminal ileum, which was biopsied, revealing a neuroendocrine tumor (NET). He was treated with palliative octreotide and chemoembolization of liver metastases until disease progression. The case highlights the importance of considering functional NETs, especially carcinoid syndrome, in patients with chronic unresolving diarrhea, since early diagnosis allows for further treatment options that can prolong survival.
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PMID:A cause to consider for chronic unresolving diarrhea. 2532 16

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT3 receptor (Ki approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the Ki value for the 5-HT3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6-4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT: There is a lack of effective current treatment for diarrhea-predominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT3 receptor is thought to be implicated in the pathophysiology. Because 5-HT3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.
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PMID:CSTI-300 (SMP-100); a Novel 5-HT3 Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome. 3210 19

Small bowel neuroendocrine tumours (NET) are relatively rare malignancies. Due to the lack of specificity, the symptoms are usually initially attributed to irritable bowel syndrome. Frequently there is a delay of years after the onset of symptoms, before the diagnosis is made. We describe two patient cases with a small bowel NET that illustrate the typical course of the symptoms, as well as the complications of carcinoid syndrome, carcinoid heart disease, mesenteric venous congestion and arterial ischemia. On coloscopy the primary tumour can often not be reached. CT scan is the best diagnostic modality and should be considered in a patient with abdominal pain, diarrhoea, weight loss and a negative coloscopy, especially in the presence of flushing. In a non-curative situation, first-line treatment consists of a somatostatin analogue, in order to prolong progression-free survival and reduce hormonal hypersecretion. Palliative surgery can also play an important role in the management of small bowel NET.
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PMID:[Small bowel neuroendocrine tumours: to be considered in the differential diagnosis of unexplained abdominal pain and diarrhoea]. 3218 28