Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lubiprostone [RU 0211, SPI 0211] is a bicyclic fatty acid that acts as a chloride channel opener, increasing intestinal water secretion. Lubiprostone, an orally-administered formulation, is one of a series of functional fatty acid compounds discovered by Dr Ryuji Ueno, and is currently undergoing development for the treatment of constipation, constipation-predominant irritable bowel syndrome (IBS-C) and postoperative ileus with Sucampo Pharmaceutical's. Lubiprostone activates a specific chloride channel (CLC2) on cells lining the gut, thereby naturally increasing intestinal fluid secretion. The increased fluid level softens the stool, promotes spontaneous bowel movements, and reduces abdominal discomfort/pain and bloating. The chloride channel is a protein that controls cell membrane transport of chloride ion. Lubiprostone acts on the ClC-2 chloride channel, which is located in the apical intestinal membrane. In November 2004, Takeda Pharmaceuticals entered into a collaboration and licensing agreement for Lubiprostone with Sucampo Pharmaceuticals for the treatment of chronic constipation and constipation-predominant Irritable Bowel Syndrome (c-IBS). Under the terms of the agreement, Takeda received the right to market the product in the US and Canada, while Sucampo reserved the co-promotion rights for these countries. Takeda's wholly-owned US subsidiary, Takeda Pharmaceuticals North America Inc., will sell lubiprostone once the product is approved by the US FDA. Takeda will also receive an option for marketing rights in other territories, including Japan and Europe. Takeda and Sucampo agreed on the exclusive manufacturing and supply of Lubiprostone by R-Tech Ueno, Ltd, a member of the Sucampo Group. Sucampo has the potential to receive up to dollar US 210 million in initial and milestone payments, some of which are contingent upon the successful achievement of several milestones. Takeda will fund a major part of development costs not only for chronic constipation and c-IBS, but also for other indications in the gastroenterology field. Takeda will make royalty payments to Sucampo after the product is launched. In May 2005, Sucampo received dollar US 20 million from Takeda Pharmaceutical as payment for achieving a development milestone of initiating a phase III clinical trial of lubiprostone to treat patients with constipation-predominant irritable bowel syndrome. Sucampo Pharmaceuticals submitted a new drug application (NDA) for lubiprostone to the FDA on 31 March 2005 for approval in the treatment of chronic idiopathic constipation (CIC) and associated symptoms in adults. Sucampo completed three long-term, open-label safety studies, which will support the NDA for lubiprostone, in treating constipation. Results from its second open-label safety study with lubiprostone were announced in February 2004, with the first two studies demonstrating long-term safety and sustained effectiveness in constipated subjects. In the US, the final phase III study for chronic constipation was completed in the fourth quarter of 2004. In November 2004, Sucampo announced completing a phase II safety and efficacy study of lubiprostone for the treatment of IBS-C. This study, which was initiated in April 2003, randomised 195 patients with documented IBS into four treatment groups (three doses of SPI 0211 and placebo) from 19 locations throughout the US.
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PMID:Lubiprostone: RU 0211, SPI 0211. 1599 86

This study sought to identify brain regions that underlie symptom changes in severely affected IBS patients undergoing cognitive therapy (CT). Five healthy controls and 6 Rome II diagnosed IBS patients underwent psychological testing followed by rectal balloon distention while brain neural activity was measured with O-15 water positron emission tomography (PET) before and after a brief regimen of CT. Pre-treatment resting state scans, without distention, were compared to post-treatment scans using statistical parametric mapping (SPM). Neural activity in the parahippocampal gyrus and inferior portion of the right cortex cingulate were reduced in the post-treatment scan, compared to pre-treatment (x, y, z coordinates in MNI standard space were -30, -12, -30, P=0.017; 6, 34, -8, P=0.023, respectively). Blood flow values at these two sites in the controls were intermediate between those in the pre- and post-treatment IBS patients. Limbic activity changes were accompanied by significant improvements in GI symptoms (e.g., pain, bowel dysfunction) and psychological functioning (e.g., anxiety, worry). The left pons (-2, -26, -28, P=0.04) showed decreased neural activity which was correlated with post-treatment anxiety scores. Changes in neural activity of cortical-limbic regions that subserve hypervigilance and emotion regulation may represent biologically oriented change mechanisms that mediate symptom improvement of CT for IBS.
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PMID:Cognitive therapy for irritable bowel syndrome is associated with reduced limbic activity, GI symptoms, and anxiety. 1603 4

Corticotropin-releasing factor (CRF) receptors have been reported to play a role in tonic colorectal distension (CRD)-induced activation of locus coeruleus (LC) neurons. We examined the influence of repeated phasic CRDs and intracisternal (ic) CRF on the spontaneous discharge rate of LC neurons in chloral hydrate-anesthetized rats and the role of CRF receptors using the nonselective CRF(1)/CRF(2) antagonist, astressin, and the water-soluble CRF(1) receptor antagonist, NBI-35965. Two consecutive phasic CRDs (43.7 +/- 1.1 mm Hg, 30 s each) at a 10-min interval increased LC activity to 184.9 +/- 15% and 171.9 +/- 12.2%, respectively. There was no difference in magnitude, onset (within 1 s), and duration (5-7 min) of the LC responses between the 1st and 2nd CRDs. CRF (300 ng/rat, ic) injected 10 min after the 2nd CRD increased LC activity to 191.1 +/- 11.2%. Astressin (3 mug, ic) completely blocked the 2nd CRD- and ic CRF-induced LC activation. Neither ic vehicle nor astressin influenced basal LC neuronal activity. NBI-35965 (10 mg/kg, iv) prevented the 2nd CRD- and ic CRF-induced LC neuronal activation, while at 5 mg significantly reduced the LC response to the 2nd CRD by 80%, but did not block that of ic CRF injected 30 min later. These findings indicate a primary role of brain CRF interacting with CRF(1) receptors in mediating the activation of LC neurons in response to a phasic CRD within the nociceptive range (>40 mm Hg). This activation may have relevance to irritable bowel syndrome characterized by lower pain threshold to CRD and hypervigilance to colonic input.
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PMID:The CRF(1) receptor antagonist, NBI-35965, abolished the activation of locus coeruleus neurons induced by colorectal distension and intracisternal CRF in rats. 1609 71

Hydrogen sulfide (H(2)S) functions as a neuromodulator, but whether it modulates visceral perception and pain is unknown. Cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) mediate enzymatic generation of H(2)S in mammalian cells. Here we have investigated the role of H(2)S in modulating nociception to colorectal distension, a model that mimics some features of the irritable bowel syndrome. Four graded (0.4-1.6 ml of water) colorectal distensions (CRDs) were produced in conscious rats (healthy and postcolitic), and rectal nociception was assessed by measuring the behavioral response during CRD. Healthy rats were administered with sodium hydrogen sulfide (NaHS) (as a source of H(2)S), L-cysteine, or vehicle. In a second model, we investigated nociception to CRD in rats recovering from a chemically induced acute colitis. We found that CBS and CSE are expressed in the colon and spinal cord. Treating rats with NaHS resulted in a dose-dependent attenuation of CRD-induced nociception with the maximal effect at 60 micromol/kg (p < 0.05). Administration of L-cysteine, a CSE/CBS substrate, reduced rectal sensitivity to CRD (p < 0.05). NaHS-induced antinociception was reversed by glibenclamide, a ATP-sensitive K(+) (K(ATP)) channel inhibitor, and N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric-oxide (NO) synthase inhibitor. The antinociceptive effect of NaHS was maintained during the resolution of colon inflammation induced by intrarectal administration of a chemical irritant. In summary, these data show that H(2)S inhibits nociception induced by CRD in both healthy and postcolitic rats. This effect is mediated by K(ATP) channels and NO. H(2)S-releasing drugs might be beneficial in treating painful intestinal disorders.
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PMID:Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels. 1938 39

Stress plays an important role in the development of visceral hypersensitivity, a key mechanism underlying the pathophysiology of the irritable bowel syndrome. Visceral sensitivity in rats is generally assessed under restrain conditions. To avoid this potential stress factor, we developed a model using implanted radio telemetry for remote measurement of the visceromotor response (VMR) to colorectal distention (CRD). Ten days after implantation of a radio telemetry transmitter and EMG electrodes, visceral sensitivity was evaluated by applying a standardized distension protocol (1, 1.5 and 2 mL) on three different days. In a second series, visceral sensitivity was assessed in maternally separated rats before, directly after and at 6 and 24 h after water avoidance (WA) stress. CRD resulted in a reproducible VMR response on the three different study days. In separated but not in non-handled rats, WA significantly increased visceral sensitivity at 6 h (P=0.006) and 24 h (P=0.004) after WA. Our results show that radio telemetry is a reliable and well tolerated new tool for evaluating visceral sensitivity in rats. These data further confirm that maternal separation is a good model for evaluating the mechanisms underlying visceral hypersensitivity.
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PMID:Assessment of visceral sensitivity using radio telemetry in a rat model of maternal separation. 1633 99

Irritable bowel syndrome (IBS) is the world's most common gastrointestinal functional disorder and is associated with several social and economic costs. Health-related quality of life is often impaired in patients with IBS. The pathophysiologic mechanisms underlying IBS remain poorly defined. The therapeutic approach to patients with IBS is based on symptoms, and fibers may play an important role in treatment. Among the various types of fiber, water-soluble, non-gelling fibers seem to be a promising option for treatment of IBS. Partially hydrolyzed guar gum (PHGG) is a water-soluble, non-gelling fiber that has provided therapeutic benefits. In clinical trials, PHGG decreased symptoms in constipation-predominant and diarrhea-predominant forms of IBS and decreased abdominal pain. Further, an improvement in quality of life was observed in patients with IBS during and after treatment with PHGG. Moreover, PHGG seems to have prebiotic properties because it increases the colonic contents of short-chain fatty acids, Lactobacilli, and Bifidobacteria.
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PMID:Role of partially hydrolyzed guar gum in the treatment of irritable bowel syndrome. 1641 51

Fibromyalgia is a chronic syndrome, characterized by widespread body pain and pain at specific tender points, whose etiology and pathogenesis is still unknown. Patient can also exhibit a range of other symptoms including irritable bowel syndrome, chest pain, anxiety, fatigue, sleep disturbance, headache. The prevalence of fibromyalgia ranges from 1-3% in the general population, and the condition is more common among female than males. Contrary to the situation a few years ago, the most widely accepted hypothesis now evoke central nervous system mechanisms, whose local functions could influence also periferical microvascular activity at tender points. There are many findings supporting the hypothesis of different endogenic and exogenic factors that lead to chronic local hypoxia in muscle tissue. Currently, therapy is polipragmatic and is aimed at reducing the pain. A range of medical treatment had been used to treat fibromyalgia. Pharmacological therapy aims to enhance the pain threshold and to support sleep. Nonpharmaceutical treatment modalities, such as exercise, massage, idrotherapy can be helpful. Future studies should investigate the possible benefits of new strategies that may combine the effects of hot pool water, stretching exercises, massage and relaxation benefits of balneotherapy.
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PMID:[Fibromyalgic syndrome: new perspectives in rehabilitation and management. A review]. 1651 4

Antimicrobial peptides are fundamental effector molecules of innate immunity, utilized in host defence by virtually all organisms studied. These gene-encoded peptides have direct antibiotic activity against a wide range of bacteria and other microbes. In humans and other mammals, defensins are a predominant class of such peptides. In the mammalian small intestine, Paneth cells, specialized secretory epithelial cells located at the base of the crypt invaginations lining the intestinal wall, produce defensins and other antibiotic proteins. Recent investigations in murine models provide compelling support for the hypothesis that enteric defensins play a pivotal role in defence from food- and water-borne pathogens in the intestinal lumen. Investigations by others indicate that intestinal commensal bacteria are key factors in the pathogenesis of IBD (inflammatory bowel disease) in genetically susceptible humans. Recent studies provide evidence that reduced expression of Paneth cell defensins may be a key factor in the pathogenesis of ileal Crohn's disease, a subgroup of IBD. Future studies to further define the function and regulation of Paneth cell defensins will enhance our understanding of normal small bowel physiology, and probably contribute to a better understanding of the pathogenesis of inflammatory and infectious diseases of the bowel. Such knowledge may provide new therapeutic targets and strategies.
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PMID:Paneth cell defensins: key effector molecules of innate immunity. 1654 89

Acupuncture has long been used for patients with irritable bowel syndrome. However, it has remained unclear. The aim of this study was to testify the effect of electro-acupuncture(EA) on (1) visceral hypersensitivity induced by the mechanical colorectal irritation during postnatal development of rats, and (2) stress-induced colonic motility changes on rats with chronic visceral hypersensitivity. The abdominal withdrawal reflex (pain threshold and score) for visceral hypersensitivity and fecal pellet output for motor dysfunction were selected as two indexes for measurement. In addition, the effect of EA on 5-HT(4a) receptor and serotonin transporter (SERT) expression in the colon mucosa was analyzed semi-quantitatively through immunohistochemistry and 5-HT concentration in the colon tissue was observed through spectro-photo-fluorimeter detection, respectively. Our results showed that EA significantly elevated pain threshold, decreased the scores and also decreased fecal pellet output during water avoid stress. Furthermore, EA decreased 5-HT concentration in colon in rats with CVH and CVH rats with water avoidance stress, and increased the 5-HT(4a) and SERT expression in rats with CVH. Thus, it can be concluded that EA attenuates behavioral hyperalgesia and stress-induced colonic motor dysfunction in CVH rats via serotonergic pathway.
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PMID:Electro-acupuncture attenuates stress-induced defecation in rats with chronic visceral hypersensitivity via serotonergic pathway. 1665 Mar 87

Visceral pain processing is abnormal in a majority of irritable bowel syndrome (IBS) patients. Aberrant endogenous nociceptive modulation and anticipation are possible underlying mechanisms investigated in the current study. Twelve IBS patients and 12 matched healthy controls underwent brain fMRI scanning during the following randomised stimuli: sham and painful rectal distensions by barostat without and with simultaneous activation of endogenous descending nociceptive inhibition using ice water immersion of the foot for heterotopic stimulation. Heterotopic stimulation decreased rectal pain scores from 3.7+/-0.2 to 3.1+/-0.3 (mean+/-SE, scale 0-5) in controls (p<0.01), but not significantly in IBS. Controls differed from IBS patients in showing significantly greater activation bilaterally in the anterior insula, SII and putamen during rectal stimulation alone compared to rectal plus heterotopic stimulation. Greater activation during rectal plus heterotopic versus rectal stimulation was seen bilaterally in SI and the right superior temporal gyrus in controls and in the right inferior lobule and bilaterally in the superior temporal gyrus in IBS. Rectal pain scores were similarly low during sham stimulation in both groups, but brain activation patterns differed. In conclusion, IBS patients showed dysfunctional endogenous inhibition of pain and concomitant aberrant activation of brain areas involved in pain processing and integration. Anticipation of rectal pain was associated with different brain activation patterns in IBS involving multiple interoceptive, homeostatic, associative and emotional areas, even though pain scores were similar during sham distension. The aberrant activation of endogenous pain inhibition appears to involve circuitry relating to anticipation as well as pain processing itself.
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PMID:Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls. 1684 94


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