Emerging receptor target in the pharmacotherapy of irritable bowel syndrome with constipation

Preclinical experiments in rodent models have recently provided new information on the mechanisms underlying pain sensation in chronic visceral hypersensitivity, as well as insights into the mechanism of action of new drugs targeting abdominal pain in irritable bowel syndrome (IBS). This article describes the evidence base supporting the role of guanylate cyclase C (GC-C) activation in the modulation of gastrointestinal transit and, in particular, in visceral hypersensitivity. We propose that GC-C activation represents an important emerging target for pharmacotherapy in IBS with constipation (IBS-C), particularly given the recent regulatory approval of the GC-C agonist linaclotide as a treatment for IBS-C. More specifically, we address the following questions: “How is pain transmitted from the colon?”; “How is abdominal pain increased in IBS-C?”; “How can we reduce IBS-related abdominal pain – what drugs have been developed?”; “Does linaclotide reduce abdominal pain in animals and humans?”; and “How does linaclotide reduce abdominal pain?”     

Comorbidity in irritable bowel syndrome

BACKGROUND: Comorbid nongastrointestinal symptoms account for two-thirds of excess health-care costs in irritable bowel syndrome (IBS). OBJECTIVES: To determine whether IBS patients are at greater risk for specific comorbid disorders versus showing a general tendency to overreport symptoms; whether patients with inflammatory bowel disease (IBD) show patterns of comorbidity similar to IBS; whether comorbidity is explained by psychiatric disease; and whether excess comorbidity occurs in all IBS patients. METHODS: All 3,153 patients in a health maintenance organization with a diagnosis of IBS in 1994-1995 were compared to 3,153 age- and gender-matched controls, and to 571 IBD patients. All diagnoses in a 4-yr period beginning 1 yr before their index visit were categorized as gastrointestinal, psychiatric, or nongastrointestinal somatic. Nongastrointestinal somatic diagnoses were further divided into symptom-based versus biological marker-based diagnoses. RESULTS: Forty-eight of 51 symptom-based and 16 of 25 biomarker-based diagnoses were significantly more common in IBS versus controls. However, there were no unique associations. Bacterial, viral, and fungal infections and stroke were among diagnoses made more frequently in IBS. IBD patients were similar to controls. Greater somatic comorbidity was associated with concurrent psychiatric diagnosis. Only 16% of IBS patients had abnormally high numbers of comorbid diagnoses. CONCLUSIONS: Comorbidity in IBS is due to a general amplification of symptom reporting and physician consultation rather than a few unique associations; this suggests biased symptom perception rather than shared pathophysiology. Comorbidity is influenced by, but is not explained by, psychiatric illness. Excess comorbidity is present in only a subset of IBS patients.     

Post-infectious irritable bowel syndrome

Post-infectious irritable bowel syndrome （PI-IBS） is a common disorder wherein symptoms of IBS begin after an episode of acute gastroenteritis. Published studies have reported incidence of PI-IBS to range between 5% and 32%. The mechanisms underlying the development of PI-IBS are not fully understood, but are believed to include persistent sub-clinical inflammation, changes in intestinal permeability and alteration of gut flora. Individual studies have suggested that risk factors for PI-IBS include patients＇ demographics, psychological disorders and the severity of enteric illness. However, PI-IBS remains a diagnosis of exclusion with no specific disease markers and, to date, no definitive therapy exists. The prognosis of PI- IBS appears favorable with spontaneous and gradual resolution of symptoms in most patients.     

Post-infectious irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common disorder associated with abdominal pain or discomfort and altered bowel habits. The majority of patients describe an insidious onset of symptoms; however, a subset report a fairly precise time of onset following an attack of acute gastroenteritis. Typically, the potential acute infectious symptoms, such as fever and vomiting, resolve after several days, but abdominal discomfort, bloating, and diarrhea persist. Although the underlying mechanism of post-infectious IBS (PI-IBS) has not been established, ongoing inflammation appears to play a role, with an increase in serotonin-containing enterochromaffin cells, T lymphocytes, mast cells, proinflammatory cytokines, and intestinal permeability. Psychiatric comorbidities are less common in PI-IBS, compared with IBS patients in general; however, the prevalence of psychological disorders is still higher compared with that in the general population and is associated with a poorer prognosis. Overall, patients with PI-IBS have a slightly improved prognosis compared with those with IBS without an infectious onset.     

Post-infectious irritable bowel syndrome

Irritable bowel syndrome (IBS) affects 8% to 22% of the general population. Although patients describe an insidious onset of symptoms, including abdominal pain relieved with bowel movements, excessive intestinal gas, variable bowel habits, and abdominal bloating, a subgroup of individuals describe the onset of IBS symptoms following an episode of acute gastroenteritis, known as post-infectious IBS (PI-IBS). Several studies have demonstrated the development of IBS following infection. Risk factors for the development of PI-IBS are female sex and longer duration of initial illness. Although the underlying mechanism of PI-IBS is unclear, ongoing inflammation is clearly a factor in the pathogenesis. The underlying inflammatory process results in increased enterochromaffin cells, T-lymphocytes, intestinal permeability, colonic transit time, and a variety of immunologic abnormalities. PI-IBS patients tend to have a better prognosis than do those with idiopathic IBS, with resolution of symptoms within 5 to 6 years. Treatment is similar to that of idiopathic IBS.     

感染后肠易激综合征

越来越多的流行病学和临床资料表明早期胃肠道感染与肠易激综合征(irritable bowel syndrome,IBS)的关系密切。大部分胃肠道感染患者能够很快恢复并且无后遗症,但是仍有一部分患者会有持续性的症状,符合IBS的诊断标准,即为感染后肠易激综合征(post-infectious irritable bowel syndrome,PI-IBS)。本文综合国内外有关PI-IBS的研究进展,从PI-IBS的流行病学特征、相关危险因素、病理生理学改变以及临床特征等方面进行作一概述。     

肠易激综合征的研究方向

肠易激综合征 (ｉｒｒｉｔａｂｌｅｂｏｗｅｌｓｙｎｄｒｏｍｅ ,ＩＢＳ)是由腹部不适或腹痛伴排便异常组成的一组肠功能紊乱综合征 ,无任何器质性或异常的生化指标。过去曾被称为“过敏性结肠”、“易激结肠”或“黏液性结肠炎”等 ,现规范统称为“肠易激综合征”。国际上对该病的诊断标准曾多次研究制订 ,于 2 0 0 0年公布了最新的罗马Ⅱ诊断标准[1] 。其要点为 :(1)诊断本病首先需排除有组织结构或生化异常的器质性疾病 ;(2 )1年内至少要累积 3个月有反复发作的腹痛或腹部不适并伴有下列排便异常中的 2项指标 :①便后腹痛缓解或减轻 ,②…     

The irritable bowel syndrome

The irritable bowel syndrome (IBS) is a familiar problem in the clinic, but as a disease entity it remains ill defined. Much confusion has arisen in the past, because of the inappropriate inclusion within the category of IBS of almost any patient with unexplained abdominal discomfort. Recent work has established that IBS patients can be positively identified by a cluster of specific symptoms. With the use of these criteria, it seems likely that IBS patients suffer from a diffuse motor abnormality of the gut associated with visceral hypersensitivity; although there is no associated psychopathology, a central nervous system component to the disorder is possible. Better insight into IBS promises more effective management.     

Diagnosing irritable bowel syndrome

It is often possible to positively diagnose irritable bowel syndrome (IBS) based on a combination of multiple symptoms and their chronic nature. Both the Manning criteria and the ROME 1999 Consensus Working Party Diagnostic Criteria help in diagnosing IBS. It is important that, during the first visit, possible contributing factors, such as associated psychosocial stress or a history of mental, physical, or sexual abuse, are considered as part of the patient evaluation. Patients need to receive a clear explanation of the possible causes of symptoms, the benign nature of IBS, and the low likelihood of serious underlying disease. An interactive, positive physician-patient relationship has a beneficial effect on the course of IBS and may be associated with a decreased need for future health care visits.     

Postinfectious irritable bowel syndrome

A small but significant subgroup of patients with irritable bowel syndrome (IBS) report a sudden onset of their IBS symptoms after a bout of gastroenteritis. Population-based surveys show that although a history of neurotic and psychologic disorders, pain-related diseases, and gastroenteritis are all risk factors for developing IBS, gastroenteritis is the most potent. More toxigenic organisms increase the risk 11-fold, as does an initial illness lasting more than 3 weeks. Hypochondriasis and adverse life events double the risk for postinfective (PI)-IBS and may account for the increased proportion of women who develop this syndrome. PI-IBS is associated with modest increases in mucosal T lymphocytes and serotonin-containing enteroendocrine cells. Animal models and some preliminary human data suggest this leads to excessive serotonin release from the mucosa. Both the histologic changes and symptoms in humans may last for many years with only 40% recovering over a 6-year follow-up. Celiac disease, microscopic colitis, lactose intolerance, early stage Crohn's disease, and bile salt malabsorption should be excluded, as should colon cancer in those over the age of 45 years or in those with a positive family history. Treatment with Loperamide, low-fiber diets, and bile salt- binding therapy may help some patients. Serotonin antagonists are logical treatments but have yet to be evaluated.     

老年肠易激综合征

肠易激综合征是由腹部不适或腹痛伴排便异常组成的一组肠功能障碍性综合征,不能用任何结构异常或生化异常来解释。过去曾被称之谓“过敏性结肠”、“易激结肠”或“黏液性结肠炎”等,现规范统称之谓“肠易激综合征”（irritable bowel syndrome。IBS）^[1]。这是一种发病率高,时常影响终生的胃肠道疾病。流行病学研究提示年龄增长伴随IBS发病率减低（可能和老年人痛觉改变有关）,但1BS始终是老年人常见的胃肠道疾病。     

Management of the irritable bowel syndrome

Irritable bowel syndrome (IBS) is the most common disorder diagnosed by gastroenterologists and one of the more common ones encountered in general practice. The overall prevalence rate is similar (approximately 10%) in most industrialized countries; the illness has a large economic impact on health care use and indirect costs, chiefly through absenteeism. IBS is a biopsychosocial disorder in which 3 major mechanisms interact: psychosocial factors, altered motility, and/or heightened sensory function of the intestine. Subtle inflammatory changes suggest a role for inflammation, especially after infectious enteritis, but this has not yet resulted in changes in the approach to patient treatment. Treatment of patients is based on positive diagnosis of the symptom complex, limited exclusion of underlying organic disease, and institution of a therapeutic trial. If patient symptoms are intractable, further investigations are needed to exclude specific motility or other disorders. Symptoms fluctuate over time; treatment is often restricted to times when patients experience symptoms. Symptomatic treatment includes supplementing fiber to achieve a total intake of up to 30 g in those with constipation, those taking loperamide or other opioids for diarrhea, and those taking low-dose antidepressants or infrequently using antispasmodics for pain. Older conventional therapies do not address pain in IBS. Behavioral psychotherapy and hypnotherapy are also being evaluated. Novel approaches include alosetron; a 5-HT(3) antagonist, tegaserod, a partial 5-HT(4) agonist, kappa-opioid agonists, and neurokinin antagonists to address the remaining challenging symptoms of pain, constipation, and bloating. Understanding the brain-gut axis is key to the eventual development of effective therapies for IBS.     

肠易激综合征的治疗

肠易激综合征（Ｉｒｒｉｔａｂｌｅ ｂｏｗｅｌ ｓｙｎｄｒｏｍｅ, ＩＢＳ）是最常见的肠道运动障碍性疾病,其紊乱不仅限于结肠,且可累及小肠乃至胃、胆囊等,临床表现为腹痛和排便习惯的改变。文献上它有过许多名称,如神经性结肠炎、过敏性结肠炎、结肠痉挛、粘液性结肠炎、结肠过敏、结肠功能紊乱等等。本病的确切病因尚不清楚。很可能是包含多种疾病的“混合体”,正因为如此,对本病的治疗并无统一的“规格”。 治疗肠易激综合征的前提 治疗 ＩＢＳ应在以下前提下进行：（１）确诊;（ ２）病人诊疗程序的考虑;（３）药物与安慰剂…     

Treatment of the irritable bowel syndrome

Individualization of treatment for patients with IBS is predicated on a thorough analysis of the patient's symptoms, consideration of the reasons for seeking health care, evaluation of symptom-precipitating factors, elimination of confounding features, and the absolute knowledge of the absence of organic illness. Collecting and codifying appropriate historical data allow the physician to educate the patient with respect to the origin of his symptoms, and to enlist the patient as a partner in his future health care. There is no single, universally accepted therapeutic agent available for the treatment of the IBS patient. As a result, treatment is directed at reducing the frequency and intensity of triggering factors as well as ameliorating the symptoms when they arise. Symptoms evoked by psychologic factors may be effectively reduced by psychotherapy or hypnotherapy. Situational anxiety may be treated for brief periods by using antianxiety agents such as diazepam, chlordiazepoxide, buspirone, or similar agents. Depressive reactions may be reduced with suitable doses of antidepressant agents such as amitriptyline. Smooth muscle hyperreactivity may be dulled with small amounts of selected anticholinergics, which are usually most effective in reducing meal-induced discomfort. Peppermint oil may be of additional benefit. Gas-related symptoms require elimination of contributory dietary factors, such as lactose-containing foods, sorbitol, or fructose, as well as certain oligosaccharides. Simethecone, charcoal, or beanase may be helpful. Functional constipation is best treated with graded doses of insoluble or soluble fiber. Diarrheal episodes may be reduced with either loperamide or diphenoxylate. Careful, continued follow-up assessment of therapeutic endeavors, a sincere interest in the patient's concerns, and surveillance for intercurrent organic illness are the cornerstones of complete ongoing care.