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

In today's climate, changed lifestyles and the increased use of antibiotics are significant factors that affect the preservation of a healthy intestinal microflora. The concept of probiotics is to restore and maintain a microflora advantageous to the human body. Probiotics are found in a number of fermented dairy products, infant formula, and dietary supplements. Basic research on probiotics has suggested several modes of action beneficial for the human body and clinical research has proven its preventive and curative features in different intestinal and extraintestinal diseases. Chronic diseases cause considerable disablement in patients and represent a substantial economic burden on healthcare resources. Research has demonstrated a crucial role of nutrition in the prevention of chronic disease. Thus, positive, strain-specific effects of probiotics have been shown in diarrheal diseases, inflammatory bowel diseases, irritable bowel syndrome, and Helicobacter pylori-induced gastritis, and in atopic diseases and in the prevention of cancer. As the majority of probiotics naturally inhabit the human intestinal microflora, their use has been regarded as very safe. However, in view of the range of potential benefits on health that might be achieved by the use of some probiotic bacteria, major and thorough evaluation is still necessary. In conclusion, probiotics act as an adjuvant in the prevention and treatment of a wide variety of chronic diseases.
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PMID:Probiotics and chronic disease. 1663 35

Colorectal cancer (CRC) is still a disease with a high incidence and mortality. Prevention of (pre-) cancerous lesions of CRC by endoscopic screening is promising, but costs are high and identification of high-risk populations is difficult. Since screening both average-risk and high-risk populations for CRC has its logistic and financial limitations, new primary prevention strategies are sought. Substantial evidence has shown that non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors can reduce the incidence and mortality of CRC. However, long-term use of NSAIDs is associated with substantial gastrointestinal toxicity and may cause an exacerbation in IBD patients. Selective COX-2 inhibitors, with a better toxicity profile and no flare-up in IBD disease activity, are therefore attractive candidates for prevention. Chemoprevention with low-dose aspirin can be considered for individuals carrying a high risk for CRC. Folate supplementation is beneficial to the folate-depleted patients, since significant risk reductions for CRC are reported. Moreover, it might be applicable to the general population because it is safe, inexpensive and protects against vascular diseases. In line with drugs beneficial for multiple disease entities, statins have recently been proposed to reduce CRC risk. Ursodeoxycholic acid has been shown to decrease the incidence of colonic dysplasia in patients with ulcerative colitis and PSC and possibly reduces recurrence rates of polyps in general. Unfortunately, prospective randomized trials, in both high-risk and general population, are not available and the evidence is still controversial. Furthermore, cumulative epidemiological and observational data suggest the potential role of hormones as a chemoprotective agent. An increase in CRC in females with an early menopause, as well as a decrease of CRC in women with hormone replacement therapy justify further research into this issue. In IBD patients, both the severity and duration of the inflammation are the most evident risk factors for the development of dysplasia and subsequently cancer. Remission of inflammation, clinically, endoscopically and histologically, in IBD is the major goal. Long-term use of 5-aminosalicylates (5-ASA) has been shown to decrease the incidence of CRC and may hold the best promise as a chemoprotective agent in IBD. In parallel with primary prevention strategies in vascular medicine, the aim might be to postpone adenoma formation, for instance for 10 years, thereby achieving a significant risk reduction for CRC. In current practice, folate supplementation along with low-dose aspirin use in high-risk patients may be most attractive candidates, while future studies will have to clarify the role of these and other chemoprotective agents.
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PMID:Chemoprevention for colon cancer: new opportunities, fact or fiction? 1678 36

There remain technical challenges to the accurate prediction and diagnosis of neoplasia in IBD; therefore, prevention strategies are based on limited evidence and instead, consensus opinions and guidelines. Existing guidelines and published expert opinions are in agreement that given the increased risk of cancer in IBD and well-described associated risks, prevention strategies are warranted. The preponderance of existing prevention is focused on secondary prevention by performance of screening and surveillance colonoscopies with random biopsies to identify neoplasia and trigger surgical resection for prevention of invasive cancer and death. Substantial technical and practical challenges remain, however, and there is a great need for improved understanding of the compounded risks of neoplasia, the natural history of dysplasia, and more accurate detection and diagnostic techniques. A future approach to prevention is likely to stratify patients based on individualized risks that include, among things, the histologic degree of inflammation present. In meantime, existing guidelines should be emphasized and ongoing education of clinicians and patients must occur.
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PMID:Surveillance for cancer and dysplasia in inflammatory bowel disease. 1695 42

IBD clearly increases the risk for GI malignancies, especially CRC. The absolute number of patients that develops such malignancies is low compared with the overall cancer rate; however, younger age of onset, higher relative risk, unique clinical presentations, and problems with early diagnosis make this a serious complication of IBD. With the exception of patients with comorbid complications, such as primary sclerosing cholangitis, the prognosis is no worse for CRCs that arise as the result of IBD compared with those that arise sporadically. The prognosis remains poor for small bowel adenocarcinomas in patients who have CD, primarily because of their advanced stage at detection. Diligent surveillance is essential for early detection and treatment of IBD-related CRCs in patients with unresected colons, long-standing or extensive disease, and in those who have early-onset CD, although pundits still question whether it significantly affects prognosis and survival. Better surveillance techniques for small bowel dysplasia or malignancy in patients who have CD is needed, especially given the poor prognosis of these patients when advanced cancers are detected. Depending on the presentation and disease diagnosis, patients have several surgical treatment options and can expect good outcomes for all. When the appropriate surgical technique is used in patients who have colon or rectal cancer, along with adjuvant chemotherapy when appropriate, prognosis and function is good; however, the experience of the surgeon can affect the prognosis for IBD-related GI cancers. Surgical therapy is based not only on general oncologic principles, but also on the surgery that is appropriate for the IBD diagnosis. Resection of the mesentery and lymphadenectomy should be performed according to oncologic principles. Postoperative survival for IBD-related CRC is good, and diligent surveillance and follow-up are critical to the patient's overall prognosis.
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PMID:Surgical approaches to cancer in patients who have inflammatory bowel disease. 1695 45

The ideal chemopreventative agent, in addition to being efficacious in the prevention of cancer, must be easily administered, affordable, safe, and well tolerated, with minimal side effects. In the past decade, a growing body of literature has emerged on the prevention of CRC in patients with long-standing CD and UC. The data are not definitive and consist almost exclusively of retrospective case-control and cohort studies rather than the more rigorous prospective RCTs. 5-ASA compounds have been most thoroughly studied, and most of the existing data support the use of 5-ASA in the prevention of CRC. Although the precise dose and duration are unclear, studies suggest that chronic systemic administration of 5-ASA at a dose of at least 1.2 g/d is most likely to be effective. A beneficial effect of folate, albeit not statistically significant, has been consistently shown in every study performed for this purpose. Folate supplementation, which is safe and affordable, should also be recommended for all patients with IBD, especially those taking sulfasalazine. UDCA has been shown to exert a protective effect in most studies on patients with UC and concomitant PSC. Because this patient population is at particularly high risk for CRC, it is advisable to consider UDCA in all patients with colitis complicated by PSC. For patients without PSC, sufficient data do not exist to recommend it for the purpose of cancer prevention. Five of the six corticosteroid studies have found a beneficial effect of systemic steroids, although most did not reach statistical significance. Regardless, given the frequent and serious adverse effects associated with chronic steroid use, systemic corticosteroids should not be prescribed for this indication. Budesonide, an oral corticosteroid with minimal systemic absorption, is a potential alternative, although it has not yet been studied as a chemopreventative agent. Similarly, until the long-term safety of chronic NSAID use can be demonstrated in patients with IBD, the role of NSAIDs in chemoprevention remains undefined. Although the data are conflicting, immune-modulating medications, such as AZA, do not seem to confer any reduction in the risk of dysplasia or CRC. The data on calcium supplementation and statin use are still too limited to endorse their use for the prevention of colitis-related CRC. Chemoprevention is an area that holds great promise in the reduction of morbidity and mortality associated with IBD. Further studies, including prospective trials when possible and cost-effectiveness analyses, need to be performed to develop an optimal strategy for the reduction of cancer risk in patients with IBD.
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PMID:Chemoprevention: risk reduction with medical therapy of inflammatory bowel disease. 1695 46

Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.
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PMID:The serotonin signaling system: from basic understanding to drug development for functional GI disorders. 1724 88

The proven involvement of cytokines in the pathophysiology of IBD has led to the development of powerful, selective, anticytokine drugs--so-called biologics--as a therapy for IBD. Although the efficacy of infliximab, a chimeric monoclonal IgG1 antibody directed against tumor necrosis factor, is proven and the use of biologic agents is growing worldwide, there is concern about their long-term safety, which includes the risk of developing cancer. An increased risk of malignancies, particularly lymphoma, has been reported in some studies of infliximab-treated patients with IBD; however, the increased risk could be caused by the underlying chronic disease, severity of the disease, concomitant medications (e.g. conventional immunomodulators), infliximab itself, or all of these variables. At present, the data do not provide clear evidence for a causal association between infliximab and the increased cancer risk. In appropriately selected patients with severe, refractory Crohn's disease, the benefits of biologic therapy seem to outweigh the cancer risk. Multicenter, case-control studies in large populations, with a long-term follow-up are needed to define the outcome of patients with IBD treated with biologic therapies.
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PMID:Treatment with biologic therapies and the risk of cancer in patients with IBD. 1726 43

orBec is an oral enteric-coated tablet formulation of the corticosteroid beclometasone, which has been developed by Enteron Pharmaceuticals, a subsidiary of Corporate Technology Development (now DOR BioPharma). orBec is being developed for the treatment of gastrointestinal graft-versus-host disease (GVHD) and an NDA has been filed in the US. DOR BioPharma has also filed an MAA in Europe for the same indication.orBec is designed to reduce the need for systemic immunosuppressive drugs, thereby improving the outcome of bone marrow and stem cell transplantation.DOR BioPharma may seek a marketing partner in the US and elsewhere for orBec in GVHD and will seek a partner for other potential indications of the drug.In December 2001, Corporate Technology Development was acquired by Endorex Corporation (now DOR BioPharma). In October 1998, Enteron Pharmaceuticals (DOR BioPharma) entered into an exclusive, worldwide, royalty bearing license agreement with George B. McDonald, MD, including the right to grant sublicenses, for the rights to the intellectual property and know-how relating to orBec. In January 2007, DOR BioPharma received $US3 million under a non-binding letter of intent from Sigma-Tau Pharmaceuticals. The agreement grants Sigma-Tau an exclusive right to negotiate terms and conditions for a possible business transaction or strategic alliance regarding orBec and potentially other DOR pipeline compounds until 1 March 2007. Under the terms of the agreement, Sigma-Tau purchased $US1 million of DOR's common stock, with an additional $US2 million paid in cash. If no agreement is reached by 1 March 2007, DOR will return the $US2 million to Sigma-Tau within 60 days. DOR BioPharma received an unsolicited proposal from Cell Therapeutics, Inc. to acquire DOR BioPharma in January 2007. Because of the non-binding agreement already signed with Sigma-Tau, DOR BioPharma's board of directors cannot consider Cell Therapeutics' merger proposal at this time. orBec has been filed for approval in the US for the treatment of gastrointestinal GVHD. The US FDA accepted the NDA filing and has established a target date of 21 July 2007 for completion of review of the NDA. In November 2006, the EMEA determined that the MAA for orBec for the treatment of gastrointestinal GVHD is complete and that the review process has begun. The data provided in the MAA and NDA submissions demonstrate that orBec safely provides a lower risk of mortality compared with the current standard of care. Both filings are supported by data from two randomised, double-blinded, placebo-controlled clinical trials. The first was a 129-patient pivotal phase III clinical trial for orBec conducted at 16 bone marrow/stem cell transplant centres in the US and France. The second trial was a 60-patient phase II clinical trial conducted at the Fred Hutchinson Cancer Research Centre. In the primary endpoint of its pivotal trial, time to treatment failure through day 50, orBec failed to achieve statistical significance (p-value 0.1177). However, orBec did achieve statistical significance in the secondary endpoints of time to treatment failure through day 80, and a reduction in mortality compared with placebo. In this trial, patient survival at the prespecified endpoint of 200 days post-transplant showed a statistically significant 66% reduction in mortality among patients randomised to orBec. DOR BioPharma believes the primary endpoint was not achieved due to a higher than expected rate of treatment failures during the initial 10 days in both treatment groups. The mortality benefit in favour of orBec was confirmed in a retrospective analysis of the phase II study, in which there was a 55% reduction in mortality at 200 days post-transplant. At 1 year after randomisation, there were relatively consistent 51% and 45% reductions in the risk of mortality among patients randomised to orBec in both the phase III and phase II studies, respectively.DOR BioPharma is also conducting a phase II clinical trial to investigate orBec in the prevention of gastrointestinal GVHD. DOR BioPharma has executed an exclusive licence agreement with the University of Texas Medical Branch at Galveston for the use of oral luminally active anti-inflammatory drugs, such as orBec, for the treatment of irritable bowel syndrome.
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PMID:Beclometasone oral--DOR BioPharma. 1732 6

The loss of intestinal epithelial cell (IEC) function is a critical component in the initiation and perpetuation of chronic intestinal inflammation in the genetically susceptible host. We applied proteome analysis (PA) to characterize changes in the protein expression profile of primary IEC from patients with Crohn's disease (CD) and ulcerative colitis (UC). Surgical specimens from 18 patients with active CD (N = 6), UC (N = 6), and colonic cancer (N = 6) were used to purify primary IEC from ileal and colonic tissues. Changes in protein expression were identified using 2D-gel electrophoreses (2D SDS-PAGE) and peptide mass fingerprinting via MALDI-TOF mass spectrometry (MS) as well as Western blot analysis. PA of primary IEC from inflamed ileal tissue of CD patients and colonic tissue of UC patients identified 21 protein spots with at least 2-fold changes in steady-state expression levels compared to the noninflamed tissue of control patients. Statistical significance was achieved for 9 proteins including the Rho-GDP dissociation inhibitor alpha that was up-regulated in CD and UC patients. Additionally, 40 proteins with significantly altered expression levels were identified in IEC from inflamed compared to noninflamed tissue regions of single UC (N = 2) patients. The most significant change was detected for programmed cell death protein 8 (7.4-fold increase) and annexin 2A (7.7-fold increase). PA in primary IEC from IBD patients revealed significant expression changes of proteins that are associated with signal transduction, stress response as well as energy metabolism. The induction of Rho GDI alpha expression may be associated with the destruction of IEC homeostasis under condition of chronic intestinal inflammation.
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PMID:Differential protein expression profile in the intestinal epithelium from patients with inflammatory bowel disease. 1733 Sep 46

The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine. Moreover, animal models suggest a therapeutic value for TRPV1 antagonists in the treatment of other types of pain, including pain from cancer. We argue that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Moreover, emerging data indicate that TRPV1 antagonists could also be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome. The lack of effective drugs for treating many of these conditions highlights the need for further investigation into the therapeutic potential of TRPV1 antagonists.
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PMID:The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. 1746 95


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