Irritable bowel syndrome: an update on therapeutic modalities

Irritable bowel syndrome (IBS) is the most common condition that a physician faces in the GI clinic. Of the general population, 10 - 25% suffer from symptoms judged to be IBS. The negative impact of this disease includes not only pain, suffering and direct medical expenses but also significant social and job-related consequences. IBS can be the result of dysfunction in any part of the brain-gut axis: alterations in the CNS caused by psychological or other factors, abnormal gastrointestinal motility, or heightened visceral sensations. Diagnosis is based on either the Manning or Rome-II criteria. Education, reassurance and emotional support are the cornerstones of successful treatment. The mainstays of the current therapeutic approach continue to be: stress management strategies, dietary modification entailing addition of dietary fibre and pharmacotherapy. Pharmacotherapy is still limited to treating symptoms. Newer drugs that modulate motility or drugs that modulate visceral sensation may be useful in selected cases. Psychopharmacological agents are useful in the treatment of IBS, especially in those with psychological co-morbidity. Alternative therapies such as homeopathy, acupuncture, special diets, herbal medication and several forms of psychological treatments and hypnotherapy are sought by many patients and are now being offered by physicians as treatment options, either alone or in conjunction with conventional forms of therapy in patients with refractory symptoms.     

Irritable bowel syndrome

Irritable bowel syndrome (IBS) is a disease of unclear, complex pathophysiology characterised by abdominal pain and discomfort and altered bowel activity. It affects an estimated 10-15% of individuals worldwide and has a large impact on quality of life (QOL) and both direct and indirect healthcare costs. Symptoms of IBS are usually triggered by disruption of gastrointestinal (GI) function secondary to infection, dietary factors, lifestyle changes or psychological stress. While most currently available pharmacological treatments of IBS focus on symptomatic treatment of the syndrome, agents that attempt to address the pathophysiology of the disease, in particular the role of serotonin, have received much attention in recent years. However, there is growing concern that serotonergic agents as a class may be associated with rare, but serious, episodes of ischaemic colitis, with several cases of this complication having been reported in association with use of serotonergic agents that have reached the market. Thus, there remains an important need for safe and effective agents that treat the symptoms of IBS. Otilonium bromide, a spasmolytic agent, has been widely used worldwide and has been found to be effective and safe for managing abdominal pain. Clinical trials indicate that it improves baseline abdominal pain and distension, and is particularly effective in reducing diarrhoea. Combining otilonium bromide with benzodiazepines, such as diazepam, may improve the efficacy of the agent with respect to GI symptoms, while also treating underlying anxiety disorders. More research is required to confirm the efficacy and mechanisms of action associated with this combination therapy in IBS. Safety data from clinical trials and postmarketing sources indicate that otilonium bromide is well tolerated, with a safety profile comparable to placebo in clinical trials and only two reported cases of adverse reactions (urticaria) among 10-year postmarketing data. This article reviews the pathophysiology and treatment of IBS with a particular focus on the role of otilonium bromide in the management of this condition.     

肠道菌群失衡与肠易激综合征

肠易激综合征（irritable bowel syndrome, IBS）是一种常见的功能性胃肠道疾病,其发病机制目前尚不完全清楚,但有越来越多的证据表明IBS可能与肠道菌群谱的改变有关。本文就IBS患者存在的结肠菌群失衡、小肠细菌过度生长及它们可能的致病机制,以及干预肠道菌群失衡等的治疗手段作一综述。     

Irritable bowel syndrome: new agents targeting serotonin receptor subtypes

Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient's symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging. The rationale for investigations on serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on the fact that serotonin, which may be released by enterochromaffin-like cells in the GI tract as well as from other sources, has a number of well documented motor effects on the GI tract and can produce hyperalgesia in several experimental models. Serotonin receptors belonging to the 5-HT3 and 5-HT4 subtype are the most extensively studied in gastroenterology, although hitherto 'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors, are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently approved for the treatment of diarrhoea-predominant IBS and is an example of a compound that, at least theoretically, may act at multiple levels: by inhibiting visceral sensitivity, by increasing compliance, and by inhibiting excitatory 5-HT3 receptors located on both ascending and descending neuronal pathways involved in peristalsis. For this reason, 5-HT3 receptor antagonists may slow transit, hence the specific indication of alosetron in diarrhoea-predominant IBS. However, alosetron has been recently withdrawn by the manufacturer because of safety concerns. Hypomotility remains an attractive therapeutic target in IBS and the new generation of prokinetics includes several partial agonists at the 5-HT4 receptor, such as tegaserod (HTF-919) and prucalopride (R0-93877). In addition, preliminary evidence suggests that 5-HT4 receptors may also be involved in the modulation of visceral sensitivity. Second-generation 5-HT4 receptor agonists seem to be devoid of the QT-prolonging effects observed in some clinical circumstances with cisapride and may be more active at the colonic level. Piboserod (SB-207266A) is a 5-HT4 receptor antagonist under development for the treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and 5-HT(1B/D) receptor subtypes stems from the observation that the former receptors mediate smooth muscle relaxation (at least in the human colon), whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract motility and visceral sensitivity.     

Current therapeutic approaches in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the gastrointestinal tract and is broadly classified into Crohn's disease (CD) and ulcerative colitis (UC). In the last decade, our understanding of the etiology and pathogenesis of this group of disorders has been improved. More specifically, recent development of biologics and use of immunomodulator agents in IBD have made it possible to robustly control mucosal inflammation and heal mucosal ulcerations and thus provide an opportunity to potentially modify disease course and prevent complications and future surgery. However, unfortunately we have not identified reliable, sensitive and specific markers to predict disease course and to identify those patients with aggressive and progressive course that would benefit from early use of biologics to prevent future complication and surgery. Thus, optimal medical management of IBD has remained multifaceted and individualized. Our primary therapeutic goals have remained unchanged and are to: [1] improve patient quality of life by treating flare ups [induction of remission], maintaining remission, and treating symptoms like diarrhea; [2] predict and prevent/treat complication; [3] prevent/treat nutritional deficiency and maintain optimal nutrition, [4] provide appropriate psychosocial support, and of course [5] attempt to modify disease course in those with aggressive disease. We can achieve these goals by appropriate use of therapeutic agents that include 5-aminosalicylates, corticosteroids, immunosuppressive agents, antibiotics, nutritional support, and the biologic agents. Information from well designed double blind placebo controlled trials combined with knowledge of the potential impact of patient and disease characteristics on disease course which can assist us to individualized treatment plan will be the guide for us to appropriately use these therapeutic agents. For example, age of the onset of the disease, patient gender and race, mode of the disease presentation, disease location, disease-associated complications such as perianal disease/fistula, and serology and genetic markers can all help to individualize disease treatment. These factors can help to determine whether one should start with 5-ASA/antibiotic/steroid [step-up where there is no risk factors for aggressive disease course] or whether one should initiate biologic therapy at diagnosis [top-down approach], and whether it is most advisable to use monotherapy with biologic treatment [e.g. in young, Caucasian male or elderly] or use a combination therapy with a biologic and an immunomodulator. Ongoing research promises, in a near future, development of more robust set of markers to be able to model disease behavior to more accurately predict disease course and thus decide on therapeutic approach with most appropriate efficacy/risk ratio for a given patient. Furthermore, current basic laboratory research has provided a large number of potential therapeutic targets to treat IBD with new promising highly specific and targeted agents.     

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.     

Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches

Diabetic microangiopathy, including retinopathy, is characterized by abnormal growth and leakage of small blood vessels, resulting in local edema and functional impairment of the depending tissues. Mechanisms leading to the impairment of microcirculation in diabetes are multiple and still largely unclear. However, a dysregulated vascular regeneration appears to play a key role. In addition, oxidative and hyperosmolar stress, as well as the activation of inflammatory pathways triggered by advanced glycation end-products and toll-like receptors, have been recognized as key underlying events_. Here, we review recent knowledge on cellular and molecular pathways of microvascular disease in diabetes. We also highlight how new insights into pathogenic mechanisms of vascular damage in diabetes may indicate new targets for prevention and treatment.     

Irritable bowel syndrome - an evidence-based approach to diagnosis

Irritable bowel syndrome (IBS) represents one of the most common reasons for primary care visits and consultation with a gastroenterologist. It is characterized by abdominal discomfort, bloating and disturbed defecation in the absence of any identifiable physical, radiologic or laboratory abnormalities indicative of organic gastrointestinal disease. IBS is a costly disorder, responsible for significant direct and indirect costs to patients and society. Much of the cost attributed to IBS arises from the time and resources used to establish the diagnosis. Historically IBS has been viewed by many as a diagnosis of exclusion rather than as a primary diagnosis, and many patients with typical symptoms will undergo an extensive array of diagnostic tests and procedures prior to the eventual diagnosis of IBS. Recent reviews addressing the management of such patients have cast doubt on the necessity for this degree of testing. Current best evidence does not support the routine use of blood tests, stool studies, breath tests, abdominal imaging or lower endoscopy in order to exclude organic gastrointestinal disease in patients with typical IBS symptoms without alarm features. Serological testing for celiac sprue in this population may eventually prove useful but validation of studies indicating an increased prevalence of this disease in patients with suspected IBS is needed. The development and refinement of symptom-based criteria defining the clinical syndrome of IBS has greatly facilitated the diagnosis of this condition, which can be confidently diagnosed through the identification of typical symptoms, normal physical examination and the exclusion of alarm features. The presence of alarm features or persistent non-response to symptom-directed therapies should prompt a more detailed diagnostic evaluation dictated by the patient's predominant symptoms.     

Psoriasis: latest advances in understanding and novel therapeutic approaches

Psoriasis is a chronic disabling skin disorder which is the end result of a pathological process involving genetic and environmental elements. Both a T-cell origin and a primary defect in keratinocytes have been considered as the starting point. Recently, transgenic animal models and severe combined immunodeficiency (SCID) grafting have been developed. Research into the basic biology and immunology of psoriasis is generating a wide range of new treatments, including differentiating agents and immunomodulatory drugs. Flaws in conducting clinical trials of psoriasis have been repeatedly described, and methodological improvements are required.     

Endothelial dysfunction and atherosclerosis: focus on novel therapeutic approaches

Endothelial dysfunction reflected by reduced nitric oxide (NO) availability is certainly the causative factor or promoting mechanism of atherosclerosis. It is necessary to detect endothelial dysfunction at an early stage using appropriate methods, and to choose a treatment for the recovery of endothelial function. There are nonpharmacological and pharmacological therapies to attain endothelial repair. The latter includes the use of renin-angiotensin system inhibitors, statins, erythropoietin, tetrahydrobiopterin, and antioxidants. The pharmacologic therapies are intended to increase NO synthase activity and NO release, inhibit NO degradation, and enhance the activity of endothelial progenitor cells. This article reviews the current knowledge of the pathophysiological events contributing to endothelial dysfunction as well as several established and novel treatment options to reverse those changes along with the discussion of recent patents.     

Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact

BACKGROUND: The impact of irritable bowel syndrome, a gastrointestinal motility disorder, is underestimated and poorly quantified, as clinicians may see only a minority of sufferers. AIM: To determine the prevalence, symptom patterns and impact of irritable bowel syndrome in the US. METHODS: This two-phase community survey used quota sampling and random-digit telephone dialing (screening interview) to identify individuals with medically diagnosed irritable bowel syndrome or individuals not formally diagnosed, but fulfilling irritable bowel syndrome diagnostic criteria (Manning, Rome I or II). Information on irritable bowel syndrome symptoms, general health status, lifestyle and impact of symptoms on individuals' lives was collected using in-depth follow-up interviews. Data were also collected for healthy controls identified in the screening interviews. RESULTS: The total prevalence of irritable bowel syndrome in 5009 screening interviews was 14.1% (medically diagnosed: 3.3%; undiagnosed, but meeting irritable bowel syndrome criteria: 10.8%). Abdominal pain/discomfort was the most common symptom prompting consultation. Most sufferers (74% medically diagnosed; 63% undiagnosed) reported alternating constipation and diarrhoea. Previously diagnosed gastrointestinal disorders occurred more often in sufferers than non-sufferers. Irritable bowel syndrome sufferers had more days off work (6.4 vs. 3.0) and days in bed, and reduced activities to a greater extent than non-sufferers. CONCLUSIONS: Most (76.6%) irritable bowel syndrome sufferers in the US are undiagnosed. Irritable bowel syndrome has a substantial impact on sufferers' well-being and health, with considerable socioeconomic consequences.