Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study

Background Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P/neurokinin‐1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS. Aim To determine whether inhibition of the neurokinin‐1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not. Methods Rome II positive IBS women were recruited for a double‐blind, placebo‐controlled, cross‐over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2‐week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed. Results Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid‐cingulate gyrus). Conclusions Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.     

Review article: gender-related differences in functional gastrointestinal disorders

Many functional gastrointestinal disorders and other chronic visceral pain disorders such as interstitial cystitis and chronic pelvic pain are more common in women than in men. In irritable bowel syndrome (IBS) there is a 2 : 1 female to male ratio in prevalence of symptoms in community samples. Female irritable bowel syndrome patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms.
While animal studies have clearly demonstrated gender-related differences in pain perception and antinociceptive mechanisms, unequivocal evidence for gender-related differences in human pain perception or modulation has only been provided recently. Gender-related differences may be related to constant differences in the physiology of pain perception, such as structural or functional differences in the visceral afferent pathways involved in pain transmission or modulation, and/or they may be related to fluctuations in female sex hormones.
Preliminary evidence suggests that female irritable bowel syndrome patients show specific perceptual alterations in regards to rectosigmoid balloon distension and that they show differences in regional brain activation measured by positron emission tomography. This preliminary evidence suggests that gender-related differences in symptoms and in the perceptual responses to visceral stimuli exist in IBS patients and can be detected using specific stimulation paradigms and neuroimaging techniques.     

CRF1 receptors as a therapeutic target for irritable bowel syndrome

The characterization of the corticotropin-releasing factor (CRF) family of neuroendocrine regulatory peptides, the cloning and pharmacological characterization of two CRF receptor subtypes (CRF(1) and CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress and the potential involvement of the CRF system in different pathophysiological conditions, including functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and psychopathologies such as anxiety/depression. Compelling pre-clinical data showed that brain CRF administration mimics acute stress-induced colonic responses and enhances colorectal distension-induced visceral pain in rats through CRF(1) receptors. Similarly, peripheral CRF reduced the pain threshold to colonic distension and increased colonic motility in humans and rodents. These observations mimic the manifestations of IBS, characterized by abdominal bloating/discomfort and altered bowel habits. Moreover, CRF-CRF(1) pathways have been implicated in the development of anxiety/depression. These psychopathologies, together with stressful life events, have high comorbidity with IBS, and are considered significant components of the disease. From these observations, CRF(1) receptors have been suggested as a target to treat IBS. Peripherally acting CRF(1) antagonists might directly improve IBS symptoms, as related to motility, secretion and immune response. On the other hand, central actions will be beneficial as to prevent the psychopathologies that co-exist with IBS and as a way to modulate the central processing of stress- and visceral pain-related signals. Here, we review the pre-clinical and clinical data supporting these assumptions, and address the efforts done at a pharmaceutical level to develop effective therapies targeting CRF(1) receptors for functional gastrointestinal disorders.     

Chronic abdominal pain in irritable bowel syndrome – current and future therapies

Introduction: Irritable bowel syndrome (IBS) is a functional gut disorder that typically manifests in early adult years. One of the two major symptoms of the disease is chronic, visceral pain. The patients report pain as the most distressing symptom with the greatest impact on quality of life, challenging both to patients and healthcare providers.

Areas covered: This review focuses on the pathophysiology of abdominal pain in IBS and describes current treatment possibilities. It also covers latest findings that may lead to novel pharmacological options in IBS pain management.

Expert commentary: Pain is the main contributor to severity in IBS. Seeking pain alleviation is the most common reason that IBS sufferers consult with their physicians. Not all patients report being satisfied with available treatments for pain in IBS and there is a pressing need to find new, more efficient therapies for this syndrome.     

Atypical antipsychotics as a possible treatment option for irritable bowel syndrome

Introduction: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder (FGID) that is characterised by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits. Although the pathophysiology of IBS is not fully understood, it is believed that psychiatric comorbidities are highly common in such patients. A variety of psychotropic medications are widely used in the treatment of IBS, particularly older antidepressants such as tricyclic antidepressants (TCAs).

Areas covered: With the advent of newer antidepressant classes with better safety and tolerability compared with TCAs, such as serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), clinicians now have more advanced treatment options for treating IBS. Additionally, some atypical antipsychotics (AAs) have recently received approval for treatment of major depressive disorder (MDD). Some AAs may have potentials based on their pharmacodynamic profile and proven benefit for mood symptoms, pain, anxiety and sleep disturbances. This article describes the potential rationale, clinical data and practical aspects involved in the use of AAs for patients with IBS.

Expert opinion: Atypical antipsychotics (AAs) may have a role in the treatment of irritable bowel syndrome (IBS) based on the currently available findings, although there is no clear evidence, and a number of clinical issues to be addressed in the use of AAs for the treatment of IBS.     

Visceral analgesics: drugs with a great potential in functional disorders?

Irritable bowel syndrome remains an incompletely understood, common syndrome with significant unmet medical needs. In IBS patients, abdominal pain is a primary factor related to quality of life impairment, symptom severity and health care utilization, and chronic visceral hyperalgesia has been identified as an important aspect of IBS pathophysiology. However, the development of therapies aimed at reducing this hyperalgesia (visceral analgesics) has been only partially successful despite preclinical evidence supporting the potential usefulness of several preclinical compounds aimed at peripheral as well as central targets.     

曲美布汀治疗肠易激综合征的临床疗效

目的 :观察曲美布汀治疗肠易激综合征(IBS)的临床疗效。方法 :参照罗马Ⅱ标准 ,选择 60例IBS病人 ,随机分成治疗组和对照组 ,每组 30例。对照组男性 12例 ,女性 18例 ,年龄 (33±s 16)a。治疗组男性 13例 ,女性 17例 ,年龄 (31± 12 )a。 2组均给予谷维素 (2 0mg ,po ,tid)、维生素B1(2 0mg ,po ,tid)、维生素C (0 .2 g ,po ,tid)。治疗组加用曲美布汀 2 0 0mg ,po ,tid ,疗程 2wk。观察治疗前后IBS腹痛、腹泻、便秘、腹胀的情况。结果 :治疗组wk 1总有效率 67% ,wk 2总有效率 83%。wk 2腹痛缓解率 90 % ,腹泻缓解率 89% ,便秘缓解率77% ,腹胀缓解率 81%。无明显不良反应。结论 :曲美布汀是治疗IBS安全有效的药物     

Alosetron

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.     

Drug treatment of the irritable bowel syndrome.

Irritable bowel syndrome (IBS) is defined as a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit, and with features of disordered defecation and distension. The irritable bowel syndrome occurs in 10 to 20% of people worldwide and is very commonly encountered in clinical practice. This has encouraged the pharmaceutical industry to search for effective drug therapy. So far, a universally effective agent has not been found, and since this is a chronic, benign disorder, beginning in youth, long term drug use should be avoided. Nevertheless, if a specific IBS symptom, such as constipation or abdominal pain dominates, a specific drug may be helpful. However, tests and treatment should be minimised or even avoided in order to do no harm. A largely nonpharmaceutical approach to IBS should be taken. This approach employs drugs sparingly and then only targeted at specific and resistant symptoms.     

Implications of melatonin therapy in irritable bowel syndrome: a systematic review

Irritable bowel syndrome (IBS) is a highly prevalent chronic functional gastrointestinal (GI) disorder associated with abdominal pain and change in bowel habits that its etiology is not known yet. In the recent years, melatonin has been proposed as a possible candidate. In the present work, all clinical or non-clinical data about effects of melatonin in GI tract and IBS obtained from literature without time limit up to August 2010 have been studied and reviewed. Eight clinical trials were reviewed for efficacy and disturbance of melatonin in IBS and other GI disorders. The results showed disturbances in endogenous melatonin concentration in IBS patients and significant benefits of exogenous melatonin in these patients by decreasing abdominal pain and improvement of overall IBS symptom scores. The results of seventeen non-clinical studies showed anxiolytic, anti-inflammatory, anti oxidative and motility regulatory effects of melatonin on GI tract. In conclusion melatonin can be a target of interest in IBS because of its potentials to regulate GI motility.     

Clinical trial: the efficacy of alverine citrate/simeticone combination on abdominal pain/discomfort in irritable bowel syndrome ‐ a randomized,double‐blind,placebo‐controlled study

Aliment Pharmacol Ther 31 , 615–624

Summary

Background Alverine citrate and simeticone combination has been used for almost 20 years in irritable bowel syndrome (IBS), but supportive scientific evidence of efficacy was limited. Aim To evaluate the efficacy of alverine citrate and simeticone combination in patients with IBS‐related abdominal pain/discomfort. Methods A total of 412 IBS patients meeting ROME III criteria were included in this double‐blind randomized placebo‐controlled study if their abdominal pain/discomfort intensity was at least 60 mm on a 0–100 mm visual analogue scale (VAS) during a 2‐week run‐in treatment‐free period. Patients were randomly assigned through the use of Interactive Voice Response System to receive either alverine citrate 60 mg with simeticone 300 mg three times daily or matching placebo for 4 weeks. Results The full analysis set included 409 patients (71.4% female: mean age: 46.2 ± 13.9 years). At week 4, alverine citrate and simeticone group had lower VAS scores of abdominal pain/discomfort (median: 40 mm vs. 50 mm, P = 0.047) and higher responder rate (46.8% vs. 34.3%, OR = 1.3; P = 0.01) as compared with placebo group. Patient receiving alverine citrate and simeticone reported greater global symptom improvement compared with those receiving placebo (P = 0.0001). Reported adverse events were similar in both groups. Conclusion Alverine citrate/simeticone combination was significantly more effective than placebo in relieving abdominal pain/discomfort in patients with IBS.     

Novel Side‐Chain Glucosylated and Adamantylated [Asp2/Glu2]Enkephalin Analogs: Synthesis and In Vitro Growth Inhibition of Human Tumor Cells

A series of new backbone‐modified Leu‐ and Met‐enkephalin analogs ( 13 – 20 a and b ) were synthesized. Backbone manipulations involved the replacement of the Gly² residue in Tyr‐Gly‐Gly‐Phe‐Leu/Met with side‐chain glucosylated or adamantylated D /L ‐aspartic or ‐glutamic acids. The in vitro antiproliferative activity of these compounds was evaluated for several cell lines and the results were compared with the effect of Met‐enkephalin, the native opioid growth factor. The tested compounds modestly inhibited the growth of the tumor cells (20–50% inhibition at millimolar concentrations). Among the tested compounds, Tyr‐D ‐Glu(AdNH)‐Gly‐Phe‐Met ( 20b ) showed significant antiproliferative activity, somewhat more pronounced on MCF‐7 (breast carcinoma) and MOLT‐4 (lymphoblastic leukemia) cells.     

Review article: the functional abdominal pain syndrome

Aliment Pharmacol Ther 2011; 33: 514–524

Summary

Background Functional abdominal pain syndrome (FAPS) is a debilitating disorder with constant or nearly constant abdominal pain, present for at least 6 months and loss of daily functioning. Aim To review the epidemiology, pathophysiology and treatment of FAPS. Methods A literature review using the keywords: functional abdominal pain, chronic abdominal pain, irritable bowel syndrome and functional gastrointestinal disorders. Results No epidemiological studies have focused specifically on FAPS. Estimates of prevalence range from 0.5% to 1.7% and tend to show a female predominance. FAPS pathophysiology appears unique in that the pain is caused primarily by amplified central perception of normal visceral input, rather than by enhanced peripheral stimulation from abdominal viscera. The diagnosis of FAPS is symptom‐based in accordance with the Rome III diagnostic criteria. These criteria are geared to identify patients with severe symptoms as they require constant or nearly constant abdominal pain with loss of daily function and are differentiated from IBS based on their non‐association with changes in bowel habit, eating or other gut‐related events. As cure is not feasible, the aims of treatment are reduced suffering and improved quality of life. Treatment is based on a biopsychosocial approach with a therapeutic patient–physician partnership at its base. Therapeutic options include central nonpharmacological and pharmacological modalities and peripheral modalities. These can be combined to produce an augmentation effect. Conclusion Although few studies have assessed functional abdominal pain syndrome or its treatment specifically, the treatment strategies outlined in this paper appear to be effective.     

Antinociceptive and antidiarrheal effects of pioglitazone in a rat model of diarrhoea‐predominant irritable bowel syndrome: Role of nitric oxide

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Treatments targeting the luminal gut microbiota in patients with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction affecting 4% of the world's population. Patients with IBS experience chronic or recurrent abdominal pain in combination with altered bowel habits (diarrhea and/or constipation), and have reduced quality of life. Despite the high prevalence and substantial burden of IBS, its pathophysiology is incompletely understood and remains to be elucidated. The importance of the gut microenvironment has been highlighted in IBS, as there are signs that the gut microbiota of patients differs from healthy controls. Recent studies have aimed to alter the gut microbiota and thereby, attempted to alleviate gastrointestinal symptoms in IBS patients. We highlighted recent advances in common treatments that are targeting the luminal gut microbiota in IBS.     

Post-inflammatory modification of colonic afferent mechanosensitivity

1. The present review discusses interactions between the immune and nervous systems in post-infectious irritable bowel syndrome (PI-IBS).
2. Visceral pain is the single symptom that most affects the quality of life of patients with irritable bowel syndrome (IBS), yet it is the least successfully managed. An underlying hypersensitivity of colonic afferents to mechanical stimuli has long been implicated in visceral pain in IBS, but little more is known of the physiological aetiology.
3. The PI-IBS patients are a cohort of IBS patients who attribute their symptoms to a preceding gastrointestinal infection by pathogens such as Campylobacter or Salmonella . Current evidence suggests that the immune system remains activated in these patients and contributes to their visceral hypersensitivity. This is characterized by a shift in the phenotype of circulating immune cells towards a Type 1 (Th1 predominating) state. Products from these immune cells sensitize colonic afferents to mechanical stimuli.
4. Rectal instillation of trinitrobenzene sulphonic acid induces a Th1-mediated inflammatory response, consistent with clinical observations in PI-IBS. The visceral hypersensitivity observed in this model is biphasic, with an initial onset characterized by visceral hypersensitivity correlating with histological damage followed by a delayed phase that occurs after histological recovery. Interestingly, this chronic visceral hypersensitivity is mediated by afferents in closest apposition to blood vessels, but furthest from the initial site of damage.
5. Both clinical and experimental evidence indicates that chronic dysregulation of the immune system induces visceral afferent hypersensitivity and, therefore, may be the central mechanism underlying PI-IBS.     

Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear. AIM: To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome. METHODS: Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves. RESULTS: Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18-30) and 30 (27-45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis. CONCLUSIONS: Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.     

Synthesis and biological evaluation of phosphonamidate peptide inhibitors of enkephalinase and angiotensin-converting enzyme

The effectiveness of phosphonamidate peptide analogues as inhibitors of rat kidney or human brain metalloendopeptidase (enkephalinase, E.C. 3.4.24.11) and angiotensin-converting enzyme (ACE, 3.4.14.1) has been explored with a series of enkephalin analogues in which the scissile Gly3-Phe4 amide bond has been replaced with a phosphonamidate moiety. These compounds exhibited good inhibitory potency against enkephalinase with several of the analogues having Ki values in the submicromolar range as contrasted to micromolar or higher toward ACE. Within a series of [(N-acylamino)methyl] phosphonamidates there was a dramatic decrease in inhibitory activity against enkephalinase as the N-acyl moiety was substituted with larger, more hydrophobic acyl groups. Likewise, the inhibitory activity of the [(N-acylamino)methyl] phosphonamidates against ACE was attenuated by larger phenylalkyl acyl functionalities, although not to the same degree as against enkephalinase. However, phosphonamidate pentapeptide analogues of (Leu)enkephalin and (D-Ala2,D-Leu5)enkephalin showed good inhibitory potency against both enzymes. Interestingly, these two (Leu)enkephalin phosphonamidate analogues were completely inactive in the electrically stimulated guinea pig ileum and mouse vas deferens preparations. Conformational factors that may be involved in this inactivity are discussed.     

Review article: new receptor targets for medical therapy in irritable bowel syndrome

Background  Despite setbacks to the approval of new medications for the treatment of irritable bowel syndrome, interim guidelines on endpoints for irritable bowel syndrome (IBS) trials have enhanced interest as new targets for medical therapy are proposed based on novel mechanisms or chemical entities.
Aims  To review the approved lubiprostone, two targets that are not meeting expectations (tachykinins and corticotrophin-releasing hormone), the efficacy and safety of new 5-HT₄ agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase-C agonists), bile acid modulation, anti-inflammatory agents and visceral analgesics.
Methods  Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics and efficacy.
Results  The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS and these effects are associated with pain relief. The pivotal mechanisms responsible for the abdominal pain or visceral sensation in IBS are unknown. The new 5-HT₄ agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability and high efficacy. The potential risks of agents 'borrowed' from other indications (such as hyperlipidaemia, inflammatory bowel disease or somatic pain) deserve further study.
Conclusions  There is reason for optimism in medical treatment of IBS with a spectrum of agents to treat bowel dysfunction. However, visceral analgesic treatments are still suboptimal.