Rationale for using serotonergic agents to treat irritable bowel syndrome.

PURPOSE: The role of serotonin in gastrointestinal (GI)-tract functioning, the pharmacologic rationale for using serotonergic agents in the treatment of irritable bowel syndrome (IBS), and clinical experience with novel serotonergic agents are described. SUMMARY: IBS is a common multisymptom disorder that is associated with a high socioeconomic burden. The goal of treatment is to provide rapid and sustained global relief of the multiple symptoms of IBS with a single, effective, well-tolerated agent. Traditional treatment options target single symptoms, and many patients are dissatisfied with the level of relief achieved and adverse effects. Research has revealed that serotonin is involved in three major actions in the gut: (1) mediating intestinal motility, (2) mediating intestinal secretion in the GI tract, and (3) modulating perception in the bowels. Serotonin is also a vital link in the brain-gut axis. Alterations in key elements of serotonin signaling have been demonstrated in patients with IBS. Tegaserod, a selective serotonin type 4 (5-HT(4))-receptor partial agonist, is indicated for use in women with IBS whose primary bowel symptom is constipation. Alosetron, a 5-HT(3)-receptor antagonist, is indicated for use in women with severe diarrhea-predominant IBS in whom traditional therapies have failed. The clinical usefulness of several other serotonergic agents for IBS is being investigated. CONCLUSION: The use of serotonergic agents in patients with IBS is based on the critical role that serotonin plays in the maintenance of normal gut function and brain-gut communication. Pharmacologic therapies targeting specific serotonin receptors represent an important step in the management of IBS.     

香砂六君子汤治疗肠易激综合征的探讨

目的:肠易激综合征(Irrltable Bowel Syndrome,IBS)是一种以肠道功能混乱为主要特征的慢性疾病,临床表现比较复杂、呈多样性,症状主要为结肠症状,同时还可以伴有躯体症状或其他消化道症状。它是一种消化道免疫系统障碍性综合征,症状为长期或者反复发作的腹痛、腹胀、伴有排便习惯和大便性状异常,就目前而言尚缺乏形态学、细菌学和生化学指标。其确切病因和发病机制至今还未完全阐明,其涉及的因素较多,可能与肠道感染、胃肠运动紊乱、内脏感觉异常、精神心理障碍有关,从动力、心理、感觉、炎症、免疫和激素等方面研究十分广泛,至今未达成共识。而香砂六君子汤作为治疗肠易激综合征有效的一种复方,目前的研究也很有限。本文主要从中医治疗肠易激综合征的病因病机及治法方面切入探讨一下香砂六君子汤对此类疾病治疗的看法。方法:通过对肠易激综合征的病因病机和整体论治以及辨病分型论治的讨论,用以法统方的原则分析香砂六君子汤是否体现肠易激综合征的治法。结果:香砂六君子汤的配伍组方完美体现了肠易激综合征的治法。结论:为香砂六君子汤物质基础研究和临床治疗肠易激综合征提供了理论基础。     

肥大细胞在肠易激综合征中的作用研究进展

肠易激综合征(irritable bowel syndrome,IBS)是一种多因素相互作用的胃肠道功能紊乱性疾病,全球范围内发病率较高。其发病机制复杂,如内脏高敏感、胃肠道动力异常、肠道屏障损坏、肠道免疫紊乱、神经免疫失调等。研究表明,肥大细胞(mast cells,MCs)在IBS的发生与发展中起到重要作用,在IBS治疗中也有初步尝试。该文就MCs在IBS发病机制中的作用及针对MCs的IBS治疗方案进行综述。     

Drug treatment of the irritable bowel syndrome.

Irritable bowel syndrome (IBS) is defined as a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit, and with features of disordered defecation and distension. The irritable bowel syndrome occurs in 10 to 20% of people worldwide and is very commonly encountered in clinical practice. This has encouraged the pharmaceutical industry to search for effective drug therapy. So far, a universally effective agent has not been found, and since this is a chronic, benign disorder, beginning in youth, long term drug use should be avoided. Nevertheless, if a specific IBS symptom, such as constipation or abdominal pain dominates, a specific drug may be helpful. However, tests and treatment should be minimised or even avoided in order to do no harm. A largely nonpharmaceutical approach to IBS should be taken. This approach employs drugs sparingly and then only targeted at specific and resistant symptoms.     

Review article: an integrated approach to the irritable bowel syndrome

Our understanding of the pathophysiology of irritable bowel syndrome (IBS) has evolved from a disorder of motility to a more integrated understanding of enhanced motility and visceral hypersensitivity associated with brain–gut dysfunction. Psychosocial factors contribute to the predisposition, precipitation and perpetuation of IBS symptoms, and affect the clinical outcome. Newer brain imaging techniques (e.g. PET, fMRI) may help us understand the relationship between altered emotional states with pain enhancement and other gastrointestinal symptoms. Diagnosis using symptom-based (e.g. Rome) criteria and a conservative diagnostic approach is recommended. Treatment is based on an effective physician–patient relationship and a combined pharmacological and behavioural approach. Newer medications acting at the 5-HT receptor may help in reducing pain and bowel dysfunction. For more severe pain, antidepressants may be considered.     

New insights into the pathophysiology of IBS: intestinal microflora, gas production and gut motility

Irritable bowel syndrome (IBS) is a complex disorder clinically characterized by abdominal pain and altered bowel habit. Its pathogenetic mechanisms are still incompletely known; genes, psychosocial factors, changes in gastrointestinal motility and visceral hypersensitivity are traditionally thought to play a crucial role in symptom generation. Recent studies have identified new additional factors that can interact with the established mechanisms. Dysregulation of brain-gut axis, gastrointestinal infection, low-grade infiltration and activation of mast cells in the intestinal mucosa with consequent release of bioactive substances, and altered serotonin metabolism are the emerging factors of IBS pathogenesis. Finally, modification of small bowel and colonic microflora and altered gas balance may be of relevance in at least some subgroups of IBS patients. New therapies can be developed only on the basis of a better understanding of the heterogeneous picture of the pathophysiology of IBS.     

Role of serotonin in the pathophysiology of the irritable bowel syndrome

The irritable bowel syndrome (IBS) is a complex disorder that is associated with altered gastrointestinal motility, secretion, and sensation. Serotonin (5-HT) is an important neurotransmitter and paracrine signalling molecule in the gastrointestinal tract. 5-HT release from enterochromaffin (EC) cells initiates peristaltic, secretory, vasodilatory, vagal and nociceptive reflexes. The enteric nervous system (ENS) comprises a semiautonomous effector system that is connected to the central autonomic network. Parasympathetic and sympathetic nerves modulate the ENS via afferent and efferent communications. Ongoing, bidirectional brain-gut interactions involving 5-HT pathways occur that significantly influence the effector systems. Altered 5-HT signalling may lead to both intestinal and extraintestinal symptoms in IBS. 5-HT directly and indirectly affects intestinal motor and secretory function and abnormalities may lead to either constipation or diarrhea. 5-HT modulates sensation and perception of visceral stimulation at peripheral and central sites. Therapeutic agents targeting altered 5-HT signalling may provide new, effective treatments for patients with IBS.     

Recent advances in pharmacological research on the management of irritable bowel syndrome

Irritable bowel syndrome (IBS), a common gastrointestinal (GI) disorder, is associated with various factors, including lifestyle, infection, stress, intestinal flora, and related diseases. The pharmacotherapeutic stimulation of receptors and downstream signaling pathways is effective in reducing IBS symptoms; however, it is still associated with adverse effects. Various receptors related to GI motility and visceral hypersensitivity should be considered to enhance the benefit/risk ratio of IBS treatments. This review discusses recent pharmacological advances in IBS management. Several receptors related to GI motility and abdominal pain are investigated in various angles. 5-Hydroxytryptamine (5-HT) is an important neurotransmitter that activates the colonic mucosal 5-HT₄ receptor without causing severe cardiovascular adverse effects. The clinical potential of ramosetron for diarrhea-predominant IBS has been suggested because of a lower risk of ischemic colitis than conventional 5-HT₃ receptor antagonists. Toll-like receptors (TLRs), especially TLR2 and TLR4, show a significant effect on the post-infection symptoms and lipopolysaccharide-mediated regulation of GI motility. Histamine is a well-known nitrogenous compound that regulates inflammatory responses and visceral hypersensitivity. Histamine 1 receptor-mediated sensitization of the transient receptor potential vanilloid 1 is associated with IBS. Pharmacological approaches based on these signaling pathways could be useful in the development of novel IBS treatments.     

Systematic review: the efficacy of treatments for irritable bowel syndrome--a European perspective

BACKGROUND: Irritable bowel syndrome (IBS) is a common, chronic disorder, characterized by abdominal pain/discomfort, bloating and altered bowel habit. AIM: To conduct a systematic evidence-based review of pharmacological therapies currently used, or in clinical development, for the treatment of IBS in Europe. The safety and tolerability of these therapies are the subject of an accompanying review. METHODS: A literature search was completed for randomized controlled studies which included adult patients with IBS and an active or placebo control, assessed IBS symptoms, and were published in English between January 1980 and June 2005. The level of evidence for efficacy was graded according to the quality of the trial design and the study outcome. RESULTS: There is some evidence for improvement of individual IBS symptoms with antidiarrhoeals (diarrhoea), antispasmodics (abdominal pain/discomfort), bulking agents (constipation), tricyclic antidepressants (abdominal pain/discomfort) and behavioural therapy. In contrast, there is strong evidence for the improvement of global IBS symptoms with two new serotonergic agents: the 5-HT4 selective agonist tegaserod (IBS with constipation) and the 5-HT3 antagonist alosetron (IBS with diarrhoea). Further data are required for the 5-HT3 antagonist, cilansetron, and the mixed 5-HT3 antagonist/5-HT4 agonist renzapride before their utility in IBS can be appraised. CONCLUSIONS: There is limited evidence for the efficacy, safety and tolerability of therapies currently available in Europe for the treatment of IBS. Overall, there is an absence of pharmacological agents licensed specifically for the treatment of IBS subtypes, and new agents are awaited in Europe that will allow changes in clinical practice to focus on and improve global IBS symptoms.     

Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

ABSTRACT

Introduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorial etiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut microbiota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiota modulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.

Areas covered: Published articles including patients with irritable bowel syndrome reporting data about rifaximin activity and safety have been searched throughout the literature and selected.

Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting. Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulating activity. It is effective in inducing symptoms relief in patients with IBS, even after repeated treatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild and infrequent; microbial resistance is rare and transient, due to the high local concentration of the drug and to the absence of horizontal transmission. Clostridium difficile infection is not usual in patients receiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppression, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is an antibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and is not expected to interfere with drug metabolism in patients with normal hepatic function. These properties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.     

Treatments targeting the luminal gut microbiota in patients with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction affecting 4% of the world's population. Patients with IBS experience chronic or recurrent abdominal pain in combination with altered bowel habits (diarrhea and/or constipation), and have reduced quality of life. Despite the high prevalence and substantial burden of IBS, its pathophysiology is incompletely understood and remains to be elucidated. The importance of the gut microenvironment has been highlighted in IBS, as there are signs that the gut microbiota of patients differs from healthy controls. Recent studies have aimed to alter the gut microbiota and thereby, attempted to alleviate gastrointestinal symptoms in IBS patients. We highlighted recent advances in common treatments that are targeting the luminal gut microbiota in IBS.     

Epidemiology,pathogenesis and treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a very common functional disorder of the gastrointestinal (GI) tract that is associated with significant healthcare costs and disability. Despite this, our understanding of this syndrome is yet limited and our treatment methods only modestly effective. The aim of this article is to review the epidemiology and pathophysiology of IBS and subsequently discuss the various treatment methods available, including current, novel and potential future therapies.     

Antinociceptive potency of enkephalins and enkephalinase inhibitors in the mouse model of colorectal distension—proof‐of‐concept

Irritable bowel syndrome (IBS) is a chronic disease characterized by abdominal pain and changes in bowel habits. Patients with IBS comprise a significant portion of attendants at the outpatient clinics. Targeting intestinal opioid receptors was found successful in alleviating pain and diarrhea—two major symptoms of IBS. In this study, we aimed to evaluate a novel potential pharmacological option: the use of enkephalinase inhibitors in therapy of visceral pain occurring in the course of IBS. We thus assessed the antinociceptive efficacy of enkephalins: Leu‐enkephalin and Met‐enkephalin, and enkephalinase inhibitors: opiorphin and sialorphin in the mouse model of visceral pain induced by colorectal distension. Leu‐enkephalin, Met‐enkephalin, and sialorphin, but not opiorphin, at the dose of 1 mg/kg injected subcutaneously potently decreased the visceromotor response to colon distension as compared to control. To conclude, enkephalinase inhibitors are worth being considered as potential therapeutics in patients with chronic abdominal pain and/or changed bowel habits, that is, suffering from IBS.     

Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life--a double-blind, placebo-controlled study

Aliment Pharmacol Ther 2011; 33: 1123–1132

Summary

Background Recent research suggests that an imbalance of the intestinal microbiota and a dysfunctional intestinal barrier might trigger irritable bowel syndrome (IBS). As probiotics have been reported to restore the intestinal microbiota and the gut barrier, the therapeutic potential of probiotics within IBS became of strong interest. Aim To assess the efficacy of Bifidobacterium bifidum MIMBb75 in IBS. Methods A total of 122 patients were randomised to receive either placebo (N = 62) or MIMBb75 (N = 60) once a day for 4 weeks. The severity of IBS symptoms was recorded daily on a 7‐point Likert scale. Results MIMBb75 significantly reduced the global assessment of IBS symptoms by ?0.88 points (95% CI: ?1.07; ?0.69) when compared with only ?0.16 (95% CI: ?0.32; 0.00) points in the placebo group (P < 0.0001). MIMBb75 also significantly improved the IBS symptoms pain/discomfort, distension/bloating, urgency and digestive disorder. The evaluation of the SF12 sum scores showed a significant gain in quality of life within the bifidobacteria group. Furthermore, adequate relief was reported by 47% of the patients in the bifidobacteria and only by 11% of the patients in the placebo group (P < 0.0001). Overall responder rates were 57% in the bifidobacteria group but only 21% in the placebo group (P = 0.0001). MIMBb75 was well tolerated and adverse events were not different from placebo. Conclusions Bifidobacterium bifidum MIMBb75 effectively alleviates global IBS and improves IBS symptoms simultaneously with an improvement of quality of life. Considering the high efficacy of MIMBb75 in IBS along with the good side‐effect profile, MIMBb75 is a promising candidate for IBS therapy.

     

中医药对炎症性肠病免疫调节的研究

炎症性肠病包括溃疡性结肠炎（UC）和克罗恩病,目前认为其是一种主要累及直结肠黏膜的自身免疫性疾病,以腹痛、腹泻、黏液脓血便、里急后重为主要临床表现,其病因和发病机制尚不明确,目前认为可能是遗传、肠道菌群、环境和免疫功能异常等多重因素共同作用所致。目前免疫应答成为研究的焦点和热点。目前炎症性肠病的西医治疗药物主要包括氨基水杨酸类、皮质激素类、免疫抑制剂和生物制剂等,这些药物或因疗效、或因副作用而使药效受限,且价格昂贵,中医药治疗凸显出较好的发展优势。本文旨在对近年来中医药治疗UC免疫调节方面发挥的作用进行综述,为以后临床上应用中医药提供一定的参考依据。     

Immune-mediated food reactions in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and an altered defecation pattern. Depending on the criteria used, it affects between 5 and 10% of the general population and has a serious impact on quality of life. Most patients with IBS show an induction or exacerbation of their symptoms, particularly abdominal pain, after eating certain foods. This raises the question of the role played by food in IBS pathophysiology. In this review, we describe the multiple risk factors of IBS, and we give an overview of the role of food as a trigger of IBS, distinguishing between immune and non-immune reactions to food. We finally highlight recent findings identifying an immune-mediated mechanism underlying food-induced abdominal pain in IBS.     

Probiotics in functional gastrointestinal disorders: what are the facts?

While a rationale for the use of probiotics can be developed for a number of functional gastrointestinal symptoms and syndromes and an experimental basis for their use continues to emerge, the only functional disorder for which an adequate database of clinical trials of probiotics to permit an assessment of clinical efficacy exists is the irritable bowel syndrome (IBS). IBS has also attracted attention, in this regard, because of recent revelations with regard to the potential roles of the enteric flora and immune activation in the pathogenesis of IBS, thereby, leading to a re-awakening of interest in bacteriotherapy in this common and challenging disorder. Some recent randomized controlled studies attest to the efficacy of some probiotics in alleviating individual IBS symptoms while selected strains have a more global impact. Evidence for long-term efficacy is also beginning to emerge though more studies are needed in this regard. Several other issues complicate the interpretation of much of the literature in this area: lack of quality control, use of many different species, and, strains and, above all, significant deficiencies in trial methodology.     

Irritable bowel syndrome: patients' attitudes, concerns and level of knowledge

BACKGROUND: Irritable bowel syndrome (IBS) is a common, chronic disorder that reduces patients' quality-of-life. Although highly prevalent, little is known about patients' understanding of this disorder. AIM: To evaluate the knowledge, fears and concerns of IBS patients. METHODS: Seven hundred thirty-six IBS patients (Rome II criteria) were eligible for inclusion in this prospective study. Each patient received a validated questionnaire to evaluate knowledge, attitudes and fears regarding IBS. RESULTS: A total of 261 of 664 potential respondents completed the questionnaire (39.3%). 83% of respondents were women, with a mean age of 53.7 years, and mean duration of symptoms of 14.2 years. Patients frequently believed that IBS develops because of anxiety (80.5%), dietary factors (75.1%) and depression (63.2%). Few respondents (28.7%) recognized that abdominal pain is the cardinal symptom of IBS, and 40.6% stated that colonoscopy can diagnose IBS. One in seven patients stated that IBS turns into cancer, and 29.9% noted that IBS increases the risk of inflammatory bowel disease. CONCLUSIONS: Many IBS patients have significant misconceptions regarding the nature of their disease and its prognosis. An overwhelming majority of IBS patients believe that anxiety, dietary factors and depression cause IBS. These findings are discordant with physicians' views and practices and highlight the need for patient-oriented educational programs.     

Characterizing abdominal pain in IBS: guidance for study inclusion criteria,outcome measurement and clinical practice

Aliment Pharmacol Ther 2010; 32: 1192–1202

Summary

Background Although irritable bowel syndrome (IBS) is a multisymptom disorder, abdominal pain drives illness severity more than other symptoms. Despite consensus that IBS trials should measure pain to define study entry and determine efficacy, the optimal method of measuring pain remains uncertain. Aim To determine whether combining information from multiple pain dimensions may capture the IBS illness experience more effectively than the approach of measuring ‘pain predominance’ or pain intensity alone. Methods Irritable bowel syndrome patients rated dimensions of pain, including intensity, frequency, constancy, predominance, predictability, duration, speed of onset and relationship to bowel movements. We evaluated the impact of each dimension on illness severity using multivariable regression techniques. Results Among the pain dimensions, intensity, frequency, constancy and predictability were strongly and independently associated with illness severity; the other dimensions had weaker associations. The clinical definition of ‘pain predominance’, in which patients define pain as their most bothersome symptom, was insufficient to categorize patients by illness severity. Conclusions Irritable bowel disease pain is multifaceted; some pain dimensions drive illness more than others. IBS trials should measure various pain dimensions, including intensity, constancy, frequency and predictability; this may improve upon the customary use of measuring pain as a unidimensional symptom in IBS.