Drug discovery approaches to irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is defined by symptoms of abdominal pain and altered bowel habits without detectable organic disease. Antidepressants and serotonin receptor modulators are used to treat IBS, but rare serious adverse events highlight the safety hurdle. Newer drugs with secretory and motility effects via local gut mechanisms have been successfully approved for IBS, often by registering first in a related, non-IBS condition to optimize dosing, formulation and therapeutic window.

Areas covered: This review looks at approaches for novel IBS drug discovery. The underlying pathologies can be tackled locally from the ‘outside-in’ (intestinal lumen, mucosa and neuromuscular) to identify therapeutic targets. The article discusses the mechanisms associated with bile acid malabsorption, microbial dysbiosis, decreased intestinal barrier function, immune dysregulation, motility and visceral hypersensitivity.

Expert opinion: Challenges for new drug discovery are the unknown mechanisms underlying IBS, making it difficult to predict clinically efficacious molecular targets, limited options for translational research and disease progression biomarkers. Drugs acting locally via multiple targets (e.g., eluxadoline [The U.S. Food and Drug Administration approved Viberzi (eluxadoline) for IBS-D on May 27th 2015], crofelemer) to validated mechanisms are proving successful with tolerable safety margins. Novel mechanisms, identified and optimized based on the emerging role of nutrient signaling, probiotics or microbial products, are promising. Therapeutic treatment earlier in disease progression may improve response and have longer term benefits.     

Drug treatment options for irritable bowel syndrome: managing for success

Irritable bowel syndrome (IBS) is a functional gut disorder the diagnosis of which is based on clinical symptoms as set forth by the Rome criteria. As the population ages, especially with the population of patients >75 years of age expanding greatly over the next 10 years, IBS is becoming one of the most common diseases of the elderly. Thus far, developing treatment strategies for patients with IBS has been difficult because of the lack of pharmacological targets and the wide range of symptomatology. Additionally, demonstration of a therapeutic benefit is difficult in the presence of a high placebo response observed regardless of the therapy employed. Fibre, antidiarrhoeals and antispasmodics all play some role in the symptomatic treatment of IBS. With the evolution of IBS as a disorder of visceral hypersensitivity, new drugs have been developed that target the enteric nervous system. Tricyclic antidepressants (TCAs) have been found to target the enteric neurons and play a role in pain modulation. Currently, the TCAs are recommended only for severe cases of IBS pain. The newest class of drugs to be approved for use in IBS are the serotonin (5-hydroxytryptamine; 5-HT) antagonists. Specifically, the 5-HT3 receptor antagonists have been shown to decrease symptoms in female patients with IBS. A related class of drugs, the 5-HT4 receptor agonists, is being developed for the treatment of constipation-predominant IBS. Further investigation into the role of spinal afferent neurons in visceral hypersensitivity is at the forefront of IBS research. Several experimental drug therapies for IBS are also discussed in this review including N-methyl-D-aspartate receptor antagonists, neurokinin-1 receptor antagonists, octreotide, clonidine and the selective M3 receptor antagonist, zamifenacin.     

The treatment of irritable bowel syndrome

The efforts of clinical researchers, lay organizations and pharmaceutical companies have increased the public profile of irritable bowel syndrome and made it a respectable diagnosis. Diagnostic symptom criteria encourage a firm clinical diagnosis, which is the foundation of a logical management strategy. This begins with education. Reassurance that no structural disease threatens should be tempered with the reality that symptoms are likely to recur over many years. Patients expect diet and lifestyle advice, even if this is not specific to irritable bowel syndrome. Only a few of those with irritable bowel syndrome see doctors, and even fewer see specialists. Therefore, the treating physician should ascertain the reason for the visit, the patient's fears and the presence of any comorbid illness, such as depression, that might require treatment in its own right. No drug treatment is useful for all of the symptoms of irritable bowel syndrome, and many patients require no drug at all. If used, drugs should target the predominant symptom. Alosetron, a 5-HT3 antagonist, is effective in treating women with irritable bowel syndrome who also have diarrhoea. Tegaserod, a 5-HT4 agonist, is useful for women with irritable bowel syndrome who are constipated. Most patients with irritable bowel syndrome need psychological support. Reassurance, discussion and relaxation techniques can be provided by the family doctor. Difficult psychopathology may require referral to a mental health professional, and the gastroenterologist can settle diagnostic uncertainties. In all cases, successful treatment depends on a confident diagnosis and the strength of the doctor-patient relationship.     

肠易激综合征的药物治疗

肠易激综合征(IBS)是临床常见的功能性肠道疾病,其基本病因尚未完全阐明,因而目前尚缺乏特异性药物治疗手段.目前临床IBS治疗仍是以对症治疗为主的综合性治疗,包括饮食治疗、药物治疗和心理治疗等,解痉剂、止泻剂、缓泻剂、抗菌药物及微生态制剂等均能用于IBS的治疗.     

Rifaximin for the treatment of irritable bowel syndrome

Introduction: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS.

Areas covered: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed.

Expert opinion: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized.     

Rifaximin for the treatment of irritable bowel syndrome

INTRODUCTION: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS. AREAS COVERED: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed. EXPERT OPINION: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized.     

Diagnosis and treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common medical disorder characterized by symptoms of abdominal pain and bowel dysfunction. It is associated with significant disability and health care costs. A practical approach to diagnosis is the symptom-based Rome criteria. Management of patients has been helped by recent findings relating to the epidemiology, pathophysiology and psychosocial contributions of the disorder. Dysregulation of intestinal motor, sensory and central nervous system function is currently believed to be the basis for IBS symptoms. Symptoms are due to both abnormal intestinal motility and enhanced visceral sensitivity. Psychosocial factors are not a cause but can affect the illness experience and clinical outcome. Finally, treatment involves an effective physician-patient relationship and an integrated pharmacologic and behavioral approach that is determined by the needs of the patient, the type and severity of the symptoms and the degree of disability.     

氟西汀治疗肠激惹综合征

目的：观察氟西汀治疗肠激惹综合征的疗效。方法：治疗组５６例（男性１９例，女性３７例，年龄４３±ｓ１２ａ），给氟西汀２０ｍｇ，ｐｏ，ｔｉｄ；对照组５２例（男性１７例、女性２５例，年龄４２±１１ａ），给维生素Ｂ１２０ｍｇ、谷维素２０ｍｇ，ｐｏ，ｔｉｄ，对腹痛、腹泻较重者另加山莨菪碱１０ｍｇ，ｐｏ，ｔｉｄ。２组疗程均为４ｗｋ。观察治疗前后症状、大便次数及性状等。结果：治疗组总有效率９５％，比对照组总有效率５６％显著提高（Ｐ＜０．０１）。结论：氟西汀治疗肠激惹综合征有显著疗效。     

Diltiazem in the treatment of the irritable bowel syndrome

A short-term double-blind study has been conducted to evaluate the clinical efficacy of diltiazem in 18 patients with irritable bowel syndrome, divided into two groups: group A, on the sequence placebo-diltiazem-placebo for three weeks. Group B, diltiazem-placebo-diltiazem for an identical period. The substance was administered in three daily doses of 60 mg prior to meals. Clinical manifestations and the general condition were evaluated after each period of three weeks following a pre-established score. Globally, it has been impossible to demonstrate the superiority of diltiazem over the placebo, but there seems to exist a trend to the improvement of diarrhoea and abdominal pain. It will be necessary to make an additional study to delineate the efficacy of this drug in the irritable bowel syndrome.     

Drug evaluation: Pumosetrag for the treatment of irritable bowel syndrome and gastroesophageal reflux disease

Dynogen Pharmaceuticals Inc, under license from Mitsubishi Pharma Corp, is developing pumosetrag (MKC-733, DDP-733), an orally available gastroprokinetic agent and locally acting 5-HT3 partial agonist, for the potential treatment of irritable bowel syndrome (IBS) with constipation and nocturnal gastroesophageal reflux disease (GERD). In September 2005, Dynogen commenced a phase II proof-of-concept trial of pumosetrag in IBS with constipation; positive results were reported in February 2007 and a phase IIb trial was to start in the fourth quarter of 2007. In September 2006, the company had initiated a phase Ib trial in nocturnal GERD.     

Novel therapies in the treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is characterised by abnormalities in motility, sensation and perception. It is one of the most common conditions encountered in clinical practice, especially by gastroenterologists. Pharmacological treatment of IBS is aimed at the predominant symptom and recent advances in pathophysiology has opened the door to the development of new compounds that target specific receptors. During this review, the most promising investigational and recently approved drugs will be discussed.     

New horizons in the treatment of irritable bowel syndrome

Irritable bowel syndrome is one of the most common diseases in gastroenterology clinics. Bowel movement is controlled by many factors such as gastrointestinal hormones and gut brain system, which are too complicated to evaluate by clinical investigation. Therefore, IBS is diagnosed on the basis of the Rome diagnostic criteria, after excluding organic gastrointestinal diseases. The basic principle in the therapy of IBS is to centrally stabilize the mental state and locally normalize intestinal function, in addition to regular daily life and dietary guidance.     

Rifaximin for the treatment of diarrhoea-predominant irritable bowel syndrome

Introduction: Rifaximin is a non-absorbable, semisynthetic antibiotic that acts as an inhibitor of bacterial RNA synthesis, with a broad spectrum of antibacterial activity. Due to its poor absorption, rifaximin has an increased exposure to the intestine, thus it is suitable for the treatment of many gastrointestinal (GI) diseases. In irritable bowel syndrome (IBS) pathogenesis, gut microbiota impairment may play a major role. The possibility of modulating intestinal bacteria using antibiotics, in particular, rifaximin, has been demonstrated to improve IBS symptoms in non-constipation subtypes of IBS.

Areas covered: We reviewed the use of rifaximin in diarrhoea-predominant IBS, focusing on its pharmacokinetic characteristics, its absorption in GI disease, its lack of interaction with other drugs and its new extended release formulation.

Expert opinion: Rifaximin, with its low systemic absorption and no clinically significant interactions with other drugs, may represent a treatment of choice for IBS, mainly due to its ability to act on IBS pathogenesis, through the modulation of gut microbiota. Further studies to analyse the effect of rifaximin treatment on the composition of faecal microbiota are warranted. In particular, they need to evaluate whether resistant bacterial strains are selected and whether they are still present in the faecal sample even a long time after therapy.     

Novel therapies in the treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is characterised by abnormalities in motility, sensation and perception. It is one of the most common conditions encountered in clinical practice, especially by gastroenterologists. Pharmacological treatment of IBS is aimed at the predominant symptom and recent advances in pathophysiology has opened the door to the development of new compounds that target specific receptors. During this review, the most promising investigational and recently approved drugs will be discussed.     

Evaluation of drug treatment in irritable bowel syndrome

The irritable bowel syndrome (IBS) remains a therapeutic challenge in part because of the limited understanding of the pathophysiology. The placebo response rate varies in randomized controlled trials from 20 to 70%, and can persist for up to at least 1 year. It is contentious whether dietary fibre and bulking agents relieve the symptoms of IBS; constipation probably improves. Anticholinergic and antispasmodic agents are of questionable benefit in IBS despite positive meta-analyses of poor quality trials. A meta-analysis concluded that the tricyclic antidepressants were superior to placebo in IBS, although the individual trial results were variable. Selective serotonin reuptake inhibitors are of uncertain benefit. Laxatives are used for constipation but probably poorly control the IBS symptom complex. Loperamide is superior to placebo in improvement of diarrhoea but not abdominal pain in IBS. Tegaserod is a well- tolerated aminoguanidine indole derivative of serotonin that is a partial 5HT4-receptor agonist with prokinetic properties; a therapeutic gain over placebo of 5% to 15% has been observed in constipation-predominant IBS in females. Alosetron is a 5HT3-receptor antagonist that is efficacious in females with diarrhoea-predominant IBS, with a 12% to 17% therapeutic gain; the risk of ischaemic colitis is 1 in 350, with very severe constipation occurring in about 1 in 1000. Optimizing study design remains a challenge in IBS. New visceral analgesic and motility modifying agents, as well as anti-inflammatory agents are in trials, and hopefully additional efficacious therapeutic options for patients with IBS will soon emerge.