Alosetron and irritable bowel syndrome

Alosetron (Lotronex^®, GlaxoSmithKline) is a potent and selective 5-HT₃-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT₃ receptors on intrinsic primary afferent neurons in the mediation of the effect of alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to alosetron is currently under investigation. The most frequent adverse event associated with the use of alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of alosetron on QOL in IBS patients and the safety of treatment with alosetron, will also be covered.     

Alosetron and irritable bowel syndrome

Alosetron (Lotronex, GlaxoSmithKline) is a potent and selective 5-HT(3)-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT(3) receptors on intrinsic primary afferent neurons in the mediation of the effect of alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to alosetron is currently under investigation. The most frequent adverse event associated with the use of alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of alosetron on QOL in IBS patients and the safety of treatment with alosetron, will also be covered.     

Pathophysiology in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a distressing condition that impairs quality of life, and it deserves to be treated. It also has a large economic impact on healthcare utilization and absenteeism. IBS is a disorder in which three major mechanisms interact: altered gastrointestinal motility, increased sensory function of the intestine and psychosocial factors. The role of prior infection in the development of IBS is the subject of ongoing study. This article focuses on pathophysiological mechanisms, including the potential roles of mucosal changes and neurobiology in the development of IBS. Novel pharmacological agents are being developed to target neural mediators of IBS; they appear promising, and their role in clinical practice will be clarified with regulatory approval and clinical use.     

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.     

Serotonergic modulation and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT₃ receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac?, a 5-HT₄ receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.     

Serotonergic modulation and irritable bowel syndrome

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT3 receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac, a 5-HT4 receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.     

Food hypersensitivity and irritable bowel syndrome

Irritable bowel syndrome is a common condition but its pathophysiology remains poorly understood. Many irritable bowel syndrome patients give a history of food intolerance, but data from dietary elimination and re-challenge studies are inconclusive. Multiple aetio-pathological mechanisms have been postulated. The gut has an extensive immune system but current understanding of processing of food antigens in health and disease is limited. There is no clinically useful marker available to test for food hypersensitivity in irritable bowel syndrome. Researchers have employed both skin tests and serum immunoglobulins (IgG and IgE) as markers of food hypersensitivity in various disorders including irritable bowel syndrome, but published data are equivocal. In this article, the evidence for the role of food hypersensitivity in irritable bowel syndrome is reviewed and, based on the available data, a possible pathophysiological hypothesis has been formulated.     

帕罗西汀治疗肠易激综合征

目的 :观察帕罗西汀治疗肠易激综合征(IBS)的疗效与不良反应。方法 :63例有明显抑郁心理障碍的IBS病人随机分成 2组 ,帕罗西汀组 3 2例 (男性 1 4例 ,女性 1 8例 ;年龄 3 4a±s1 0a) ,对照组 3 1例 ,(男性 1 4例 ,女性 1 7例 ;年龄 3 4a± 1 1a) ,2组均给予硝苯地平 1 0mg、洛哌丁胺 2mg、谷维素 2 0mg ,po,tid;帕罗西汀组同时给予帕罗西汀2 0mg,po,qd;疗程为 4wk ,共 2个疗程。结果 :帕罗西汀组治疗wk 4,8末躯体症状严重度评分 (4 .8± 1 .6,3 .8± 1 .4)、抑郁量表评分 (4 0± 5 ,3 8± 7) ,生活质量评分(5 7± 1 3 ,70± 1 6) ,与对照组 (6.1± 2 .0 ,5 .8±2 .4;5 2± 7,49± 4;49± 1 6,5 1± 1 7)比较差异有非常显著意义 (P <0 .0 1 ) ;帕罗西汀组治疗wk4,8末有效率分别为 75 % ,97% ,对照组为 48% ,5 8% ,(P <0 .0 5 )。帕罗西汀组不良反应轻微。结论 :帕罗西汀治疗伴明显抑郁心理障碍的IBS病人疗效显著 ,且较安全     

Mebeverine alters small bowel motility in irritable bowel syndrome

Background and Aim : Despite its widespread use in irritable bowel syndrome (IBS), limited clinical data exist on the effects of mebeverine hydrochloride on gastrointestinal motility. Human motor activity in the small bowel is more reproducible than that in the large bowel; therefore the aim of this study was to determine in the small bowel the effects of oral mebeverine in both IBS patients and in healthy controls.
Methods : Twelve IBS patients (11 females/ 1 male, 46±13 years old)—predominant constipation (IBS-C, n =6) and predominant diarrhoea (IBS-D, n =6)—and six healthy controls, underwent continuous 48 h ambulant recording of small bowel motor activity. One low energy (400 kcal) and one high energy (800 kcal) standard meal were administered in each consecutive 24-h period. Subjects received, in blinded fashion, placebo tablets in the first 24 h then mebeverine 135 mg q.d.s. in the second 24 h.
Results : Mebeverine had no effect on parameters of small bowel motility in controls. In contrast, in both IBS-C ( P =0.01) and IBS-D ( P <0.05) patients, phase 2 motility index was increased during mebeverine administration. Also, after mebeverine the proportion of the migrating motor complex cycle occupied by phase 2 was reduced in IBS-D ( P =0.01), while phase 2 burst frequency was reduced in IBS-C ( P <0.05). For phase 3 motor activity in IBS-C patients, the propagation velocity was decreased ( P <0.01), and the duration increased ( P <0.01).
Conclusions : These findings suggest that mebeverine, in the initial dosing period, has a normalizing effect in the small bowel in IBS, enhancing contractile activity in a similar fashion to 'prokinetic' agents, as well as producing alterations in motor activity consistent with an 'antispasmodic' effect.     

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.     

Tachykinin receptor antagonists in irritable bowel syndrome

Tachykinins (TKs) are abundantly expressed in the gastrointestinal (GI) tract in intrinsic excitatory motor neurons, interneurons, sensory neurons and extrinsic sensory neurons. Their role in the regulation of enteric secretomotor functions is well established, especially following pathophysiological stimuli. Recent evidence emphasizes the role of TKs in the sensitization of peripheral branches of visceral afferent neurons, implying a role in determining visceral hypersensitivity. Furthermore, the involvement of both CNS and peripheral TK receptors in autonomic reactions to stress, render these receptors an appealing target for the development of drugs aimed at the treatment of irritable bowel syndrome (IBS), a functional GI disorder. The available preclinical evidence indicates that TK receptor antagonists could normalize motor disturbance (diarrhea and constipation) and reduce the painful symptoms that characterize IBS.