The trials and tribulations of drug development for functional gastrointestinal disorders

Abstract  Functional gastrointestinal disorders (FGID) are common conditions seen in primary care and specialty practices but many affected individuals report a lack of satisfaction with available treatments. Despite the unmet need for more effective pharmacotherapy, drug development for these conditions can be challenging on many levels. This review will discuss the rationale and challenges of drug development for FGID. The reasons for engaging in drug development include that these conditions are highly prevalent, associated with a significant economic and healthcare burden, and associated with a lack of satisfaction with current therapies. The challenges include the lack of perception that FGID are legitimate disorders, the multidimensional and complex pathophysiology of FGID, the lack of a biological marker for diagnosis and treatment response, the heterogeneity of the patient population, the lack of consensus regarding the best outcome measures for clinical trials and the perceived increased risk–benefit ratio associated with drugs for FGID. Ongoing efforts are being taken to work towards a better understanding of pathophysiology, illness severity, patient-reported outcome measures, and benefit : risk assessment, and towards increasing education and communication amongst patients, clinicians, investigators, industry and regulatory agencies which will hopefully help optimize drug development strategies for FGID.     

The patterns of small bowel motility: physiology and implications in organic disease and functional disorders

The physiology and pathophysiology of small bowel motility are reviewed with particular focus on the motility patterns and periods that are detected by intraluminal manometry. Motility patterns are groups of phasic pressure waves resulting from contractions of the circular muscle layer of the small bowel that are organized by the enteric nervous system. Phase III of the migrating motor complex, the hallmark of the fasting motility period, thus reflects enteric neuromuscular function. Response to meal challenge also involves the CNS, reflexes beyond the gut and endocrine responses. Although specific disease diagnosis cannot be made by motility studies of the small bowel, the functional integrity is revealed. The normal occurrence of the essential patterns and periods of motility and the absence of distinctly abnormal patterns evidence preserved function, whereas the opposite indicates clinically significant dysmotility. Certain motility patterns are occasionally seen both in health and disease, and increased prevalence indicates a moderate dysfunction of yet unclear significance. Bacterial overgrowth with Gram-negative bacilli is the consequence of severe small bowel dysmotility, and a diagnosis that can be predicted by a motility study. Testing can be useful in the clinical management of paediatric and adult patients also by predicting the prognosis and response to enteral nutrition and medical therapy. Further studies are, however, needed to take full advantage of motility testing in clinical practise.     

Sleep disturbances are linked to both upper and lower gastrointestinal symptoms in the general population

Abstract  In tertiary referral patients, there is association between altered sleep patterns, functional bowel disorders and altered gut motor function. Body mass index (BMI) is also associated with gastrointestinal (GI) symptoms including diarrhoea, and with sleep disturbances. Our hypothesis is that sleep disturbances are associated with GI symptoms, and this is not explained by BMI. A 48-item-validated questionnaire was mailed to 6939 community participants in Olmsted County, MN. The survey included GI symptoms, sleep disturbance, daily lifestyle and quality of life (QOL). Independent contributions of sleep disturbance to individual symptoms were assessed using logistic regression adjusting for age, gender, lifestyle and mental health status. The association of an overall sleep score with an overall symptom score was examined and the ability of both scores to predict SF-12 physical and mental functioning scores assessed in multiple linear regression models. Among 3228 respondents, 874 (27%) reported trouble staying asleep. There was a significant correlation of overall sleep scores with overall GI symptom scores (partial r  = 0.28, P  < 0.001). Waking up once nightly at least four times a month was significantly associated with pain, nausea, dysphagia, diarrhoea, loose stools, urgency and a feeling of anal blockage. Trouble falling asleep was significantly associated with rectal urgency. Associations were independent of gender, age, lifestyle factors and BMI. Overall, sleep scores and GI symptom scores were both significant independent predictors of impaired QOL. In the community, reporting poor sleep is associated with upper and lower GI symptoms, but this is independent of BMI.     

The challenge of cross-cultural, multi-national research: potential benefits in the functional gastrointestinal disorders

Abstract  The increasing interest in research in irritable bowel syndrome (IBS) and other functional gastrointestinal disorders (FGIDs), taken together with the growing sophistication of communication technology, makes cross-cultural, multi-national research a feasible endeavour. The aim of this study is to encourage collaborative cross-cultural studies in FGIDs by discussing relevant methodological issues, and by suggesting potential areas in which cross-cultural research can make a significant contribution to the understanding of FGIDs and to patient care. To this end, methodological issues related to cross-cultural research and competences required for its conduct are presented together with a critique of published studies and recommendations for future research in the area. The term 'cross-cultural' research in FGIDs is usually applied to the results of prevalence studies, for example comparative studies of IBS prevalence in different countries and ethnic groups. The validity of these comparisons is impacted negatively by the lack of uniformity in research methods. In addition to prevalence studies, cross-cultural research can make a significant contribution in areas such as molecular biology, genetics, psychosocial factors, symptom presentation, extra-intestinal comorbidity, diagnosis and treatment, determinants of disease severity, healthcare utilization, and health-related quality of life, all issues that can be affected by culture, ethnicity and race. Well-designed and implemented cross-cultural studies can advance our knowledge in many FGID-related areas ranging from epidemiology through psychosocial factors, pathophysiological mechanisms and therapeutics. These studies, conducted by investigators with competence in cross-cultural research methodology, can advance our understanding of the FGIDs and contribute to improved patient care.     

Mechanisms of hypersensitivity in IBS and functional disorders

General introduction  The concept of visceral hypersensitivity is accepted as being germane to several functional gastrointestinal disorders (FGIDs). The causes or risk factors associated with this hypersensitivity are unclear. This article addresses the proposed mechanisms leading to hypersensitivity: from genetic to inflammatory disorders, from central to peripheral alterations of function. However, in order to place visceral hypersensitivity in a more global perspective as an aetiological factor for FGIDs, it also provides a review of recent evidence regarding the role of other peripheral mechanisms (the intraluminal milieu), as also genetic factors in the pathophysiology of these disorders. The article has been divided into five independent sections. The first three sections summarize the evidence of visceral hypersensitivity as a biological marker of functional gut disorders, the peripheral and central mechanisms involved, and the role of inflammation on hypersensitivity. In opposition to visceral hypersensitivity as an isolated phenomenon in functional gut disorders, the last two sections focus on the importance of peripheral mechanisms, like motor disturbances, specifically those resulting on altered transport of intestinal gas, and alterations of the intraluminal milieu and genetics.     

Functional gastrointestinal disorders and mast cells: implications for therapy

The pathophysiology of functional gastrointestinal disorders is poorly understood. Accepted common mechanisms include psychosocial factors, abnormal gastrointestinal motility and disturbed visceral sensory perception, but the underlying causes remain unclear. Mast cells (MCs) are immunocytes widely distributed throughout the gastrointestinal tract. Several stimuli (e.g. allergens, neuropeptides and stress) lead to MC activation with consequent mediator release (e.g. histamine, tryptase and prostanoids). The MC mediators interact with nerves supplying the gut leading to altered gut physiology and increased sensory perception. The intestinal mucosa of irritable bowel syndrome patients contains on average an increased number of MCs. These cells release an increased amount of mediators in close vicinity to mucosal innervation. The MC activation and their close proximity to nerve fibres is correlated with the severity of perceived abdominal painful sensations. These data provide a strong basis for considering MCs as important participants in visceral hypersensitivity and pain perception in irritable bowel syndrome. Inhibition of MC function may ameliorate irritable bowel symptoms. Novel drugs with an increased potential in the control of MC function (e.g., anti-IgE antibodies, the intracellular protein tyrosine kinase inhibitor Syk) and mediator release (e.g., second generation antihistamines, proteinase-activated receptor antagonists) may be useful pharmacological tools for these common disorders.     

Brain–gut connections in functional GI disorders: anatomic and physiologic relationships

Understanding the neural regulation of gut function and sensation makes it easier to understand the interrelatedness of emotionality, symptom-attentive behavior or hypervigilance, gut function and pain. The gut and the brain are highly integrated and communicate in a bidirectional fashion largely through the ANS and HPA axis. Within the CNS, the locus of gut control is chiefly within the limbic system, a region of the mammalian brain responsible for both the internal and external homeostasis of the organism. The limbic system also plays a central role in emotionality, which is a nonverbal system that facilitates survival and threat avoidance, social interaction and learning. The generation of emotion and associated physiologic changes are the work of the limbic system and, from a neuroanatomic perspective, the 'mind-body interaction' may largely arise in this region. Finally, the limbic system is also involved in the 'top down' modulation of visceral pain transmission as well as visceral perception. A better understanding of the interactions of the CNS, ENS and enteric immune system will significantly improve our understanding of 'functional' disorders and allow for a more pathophysiologic definition of categories of patients currently lumped under the broad umbrella of FGID.     

Children with functional gastrointestinal disorders with and without co-existing nausea: A comparison of clinical and psychological characteristics

Background

Nausea co-existing with functional gastrointestinal disorders (FGIDs) has been suggested to negatively impact physical and psychological factors in children. This study aims to compare clinical and psychological characteristics of a large cohort of pediatric patients with an FGID with and without nausea.

Methods

Patients of two previous randomized controlled trials were included, the first assessing the effect of hypnotherapy (HT) in 260 children fulfilling Rome criteria of irritable bowel syndrome (IBS) or functional abdominal pain (FAP), the second examining the effect of HT in 100 children with nausea in children with either functional nausea (FN) or functional dyspepsia (FD). At inclusion, demographics, clinical features, including the presence of nausea, depression and anxiety, somatization, and health-related quality of life (QoL) were assessed in patients.

Key Results

In total, 355 patients with IBS (n = 131), FAP (n = 127), FN (n = 62), and FD (n = 35) were included, of which 255 (72%) patients experienced nausea versus 100 (28%) without nausea. Age at onset of symptoms was higher in children experiencing nausea (12.0y vs. 9.0y, p = 0.000). Significantly higher somatization, anxiety and depression scores, and lower health-related QoL were reported for children with nausea. There were no significant differences between children with only nausea and children with nausea and abdominal pain.

Conclusions and Inferences

Children with nausea, either with or without abdominal pain, report higher somatization scores, increased anxiety and depression, and lower overall QoL, compared to children with pain-related FGIDs without accompanying nausea. Addressing the presence of nausea in children with FGIDs seems essential to customize their treatment and improve overall quality of life.     

Patient-reported outcomes and gut dysmotility in functional gastrointestinal disorders

Background Unlike chronic idiopathic intestinal pseudo‐obstruction (CIIP), severe digestive syndromes that are not characterized by episodes resembling mechanical obstruction remain poorly characterized. The present study compared clinical features, small bowel motility, and quality of life (QoL) in patients with CIIP or severe functional gastrointestinal disorders (SFGID), compared to irritable bowel syndrome (IBS). Methods We enrolled 215 consecutive patients: 70 CIIP, 110 malnourished SFGID [body mass index (BMI) 17.8 ± 1.8 kg m^?2] and 35 non‐malnourished SFGID (BMI 22.8 ± 3.6 kg m^?2). Key Results Abnormal motor patterns that fulfilled diagnostic criteria for small bowel dysmotility were virtually absent in IBS patients, but were recorded in69 CIIP patients (98.6%), 82 malnourished SFGID patients (74.5%;), and 23 SFGID patients without malnutrition (65.7%) (P < 0.0001). CIIP patients presented more frequently abnormal activity fronts, lack of response to feeding, and hypomotility than malnourished and non‐malnourished SFGID patients (61.4%vs 42.7% and 31.4%, P < 0.05 only vs non‐malnourished SFGID; 8.6%vs 0.9% and 2.9%; 21.4%vs 0.9% and 0%, P < 0.05). Quality of life mean scores were all significantly lower in CIIP patients and malnourished SFGID patients than in IBS. Bodily pain, general health, and vitality scores were lower in CIIP also compared to non‐malnourished SFGID. Conclusions & Inferences Chronic idiopathic intestinal pseudo‐obstruction and SFGIDs are frequently associated with small bowel dysmotility and marked derangements of QoL which are significantly more severe than in IBS and result particularly in being severe in patients with recurrent sub occlusive episodes or inability to maintain a normal body weight.     

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

Abstract  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-HT₃ 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-HT₄ agonists such as Prucalopride and 5-HT₄ partial agonists such as Tegaserod.