# Possible genetic link for positive response to Lotronex identified



## jjohnson (Apr 29, 2004)

I just came across this patent application that purports to have found a genetic link that would identify patients likely to benefit from Lotronex (alosetron). DAVID J LEVY, CORPORATE INTELLECTUAL PROPERTY GLAXOSMITHKLINE FIVE MOORE DR., PO BOX 13398 RESEARCH TRIANGLE PARK NC 27709-3398 USAbstract:A method of designing human clinical drug trials in which the drug under study is administered to a defined population of test patients who have demonstrated a predisposition to responding to the study drug by virtue of their having one or more genes that have independently been determined to be associated with the desired response. --I have been unable to post the link or the article in its entirety. (This board won't accept either for some reason.) However, the patent application number is: 20040039554Be forewarned, the information in this document is fearsomely complex (and I don't claim to understand any of it), but if anyone here with some grounding in the science of IBS would like to take a crack at it (Eric?), I would love to hear their opinions.At any rate, I think it sounds like promising research.


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## eric (Jul 8, 1999)

Yes it is majorally complex, and I only understand some of it and am still studying it.It has to do with specific genes and polymorphisms. It also has to do in some studies with serotonin transportation."These funds will be used to collect DNA from a large sampleï¿½500 IBS cases and 500 matched controlsï¿½and determine whether two genetic polymorphisms are associated with IBS. Other investigators have postulated that two genes that code for the serotonin transporter protein and the b3 subunit of the G protein may play a role in the development of IBS symptoms. Other studiesï¿½ conclusions regarding these genetic polymorphisms have been limited by small sample sizes that will not be an issue in our large study. If a positive association between either of these genetic polymorphisms and IBS are found, insight will be provided into the underlying pathophysiology of IBS and future therapeutic studies could then be directed towards these specific gene protein products. An additional advantage of this study is that future genetic studies can easily be performed on DNA samples collected in this study if new candidate genes are proposed. Our ultimate goal is to create a biospecimen-linked database to identify genetic and non-genetic factors that may be responsible for IBS and predict response to therapy. Without this award, reaching these goals would not be possible. I am grateful to the FDHN for investing their resources in this project and in my academic career." http://www.fdhn.org/html/awards/solvay.html "Main Entry: polyï¿½morï¿½phismPronunciation: pï¿½l-i-mr-fiz-mFunction: noun: the quality or state of existing in or assuming different forms: as a (1) : existence of a species in several forms independent of the variations of sex (2) : existence of a gene in several allelic forms (3) : existence of a molecule (as an enzyme) in several forms in a single species b : the property of crystallizing in two or more forms with distinct structure" http://www.nlm.nih.gov/medlineplus/mplusdictionary.html The investigations are also being done to try to determine why lotronex or zelnorm for example work for some and not for others in IBS and also for new serotonin medications. But also for other reasons.


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## eric (Jul 8, 1999)

I will post some more on this very soon for you.


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## jjohnson (Apr 29, 2004)

Wow! Thanks Eric,You seem to know all about this. Maybe you deserve an honorary degree in the field of IBS research considering how much you must have studied it.Most of the research you mentioned seems to focus on the beneficial effects of these drugs. But I was wondering if there is any research along these lines to study any predisposition to their potentially harmful side-effects (like ischemic colitis.) I would think these companies would be very interested in trying to get to the bottom of that (unless of course there is some perfectly valid reason beyond my comprehension why that would be impossible.)Also, do you think this research could lead to the very idea of IBS as a single illness becoming out of date? For instance, if the dysfunction of 5-HT3 is the problem for some people, that may be its own unique illness, if the problem in others is with some other receptor (possibly under investigation or still undiscovered), that would be its own illness, etc. I would be very interested in your thoughts on that.Again, thanks for the great info.


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## jjohnson (Apr 29, 2004)

Well, it looks like at least in the case of Lotronex, this sort of research is being done to study adverse effects. In fact, the FDA required the company to do so as part of its postmarketing studies for the drug (though it also seems very much in the company's own interest as well.) http://www.nature.com/nrg/journal/v5/n9/pdf/nrg1430.pdf Hopefully all of this research will lead to discoveries that may dramatically alter the risk/benefit ratio in favor of greater access to this whole class of drugs.


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## eric (Jul 8, 1999)

Thanks, I posted a long thread and it got eaten. "Also, do you think this research could lead to the very idea of IBS as a single illness becoming out of date?"It is in a way. IBS is the result of altered motility, viceral hypersensitivity and brain gut axis dysfunction. There are subgroups, which all lead to the clinical presentation we all know as IBS. Mnay IBS patients also have a lot of things in common.There are also common non gi issuesIBS ï¿½ Beyond the Bowel:The Meaning of Co-existing Medical Problems http://www.ibsgroup.org/ubb/ultimatebb.php...c;f=10;t=001032 EC cells and Mast cells are major players.There still maybe some underlying CNS or ENC problems, in fact that is an underlying problem in IBS, the communication between the Central nervous system and the Enteric nervous system.The total reasons are not fully understood yet, in part because it is all so very complex. There is still a lot they are learning and have to learn, but in the same regard a lot they have learned and alreay know about. Also in part why Fibro, cfis and some bladder problems and non gi issues are all connected. The first line treatment approach recommend by the experts is still a holitic approach to the mind body or CNS and ENS systems."psychophysiological arousal is at the core of treating functional gi disorders. There is so much distress, anxiety and antisipatory anxiety, and negative reaction to symptoms, that treating the mind and body often makes a significant difference in symptoms."Y. Ringel, MDAssistant Professor of Medicine Y. Ringel, MD, is an experienced internist and gastroenterologist. Prior to joining the UNC medical faculty as an Assistant Professor of Medicine, Dr. Ringel completed a postdoctoral research fellowship at the Center under the mentorship of Drs. Drossman and Whitehead. He gained valuable experience in the theories and methodologies involved in research related to functional GI disorders, including the design and conduct of clinical trials, use of advanced GI physiology and motility research techniques, validated psychosocial research tools, and functional brain imaging.Dr. Ringel has helped to expand the Center's research and educational activities. His research on GI tract sensation e.g., visceral hypersensitivity focuses on physiological mechanisms in functional GI disorders, while incorporating relevant psychological contributors into the research model. Together with Dr. Drossman, Dr. Ringel is leading a brain imaging project, which is looking at the brain's response to intestinal stimulation using advanced imaging techniques with positron emission tomography PET and functional MRI. He is also investigating the effect of various physiological intestinal smooth muscle tone compliance, autonomic nervous system activity and psychosocial history of abuse factors in upper and lower GI tract sensation. And, he is involved in the design, evaluation and conduct of clinical trials evaluating new drugs and treatment approaches for functional GI disorders.Other areas of research that Dr. Ringel would like to pursue include: 1 epidemiology of FGIDs, 2 mechanism studies on GI physiological responses to pain, and 3 investigation of whether specific strains of colonic bacteria contribute to IBS symptoms and whether altering the bacterial milieu with probiotics will lead to improvement of IBS. Dr. Ringel's research work has been well recognized through the awards he has received, including among others the following: AGA Solvay Award for Clinical Research in Irritable Bowel Syndrome Motility awarded by the Foundation for Digestive Health and Nutrition; ACG Junior Faculty Development Award; and the Annual Young Investigator Award of the Functional Brain-Gut Research Group (FBG). http://www.med.unc.edu/medicine/fgidc/ringel.htm "The syndrome was once thought to be simply a visceral response to stress, because doctors could find no biological explanation. As a result, many patients felt that their doctors gave their problem short shrift or, worse, implied it was all in their heads. "People with I.B.S. are sensitized to doctors' thinking they're crazy," Dr. Fisher said. Recent studies indicate that the syndrome may arise from problems in the working of the colon and in the connection between the brain and the colon. "The brain and bowels are wired with a series of nerves," Dr. Brennan M. R. Spiegel, a gastroenterologist at the University of California, Los Angeles, said. "If you have I.B.S., you're wired up in a slightly different way, and that can cause diarrhea, constipation or pain."Studies have shown that people with the syndrome are more sensitive to colon pain and that their brains process the pain abnormally. Stress and anxiety can lead to symptoms or worsen them, but those factors do not cause the disorder, experts say.Abnormal functioning of serotonin in the colon also appears to promote irritable bowel syndrome. In the brain, serotonin is thought to influence mood. But in the colon, where 95 percent of the body's serotonin is found, it helps produce the normal contractions of peristalsis." http://www.ibsgroup.org/ubb/ultimatebb.php...c;f=10;t=001043 On the Relationship Between Colon Ischemia, Irritable Bowel Syndrome, and Serotonergic Therapy of Irritable Bowel SyndromePosted 09 24 2004 Lawrence J. Brandt, MD Introduction and ContextThe ProblemColon ischemia and irritable bowel syndrome (IBS) are 2 common gastroenterologic disorders that, until recently, were thought to occur independently in very different populations. We know now, however, that there is a complex association between the 2: (1) colon ischemia appears to be more common in the IBS patient than was recognized previously; and (2) there is concern that the newly developed serotonin receptor agonists or antagonists may increase the risk of colon ischemia, and serotonergic signaling may be abnormal in patients with colitis. This review highlights some of the relationships between colon ischemia, IBS, and therapy for IBS.IBS -- Pathophysiology and Clinical PresentationIBS is a disorder that is diagnosed by various symptom-based criteria, such as the Manning, Rome, and Rome II criteria. IBS lacks any biologic, physiologic, structural, or serologic marker, and so diagnosis is symptom-based. Symptoms typically include abdominal discomfort or pain, bloating, diarrhea, fecal urgency, and constipation. Symptoms may change with time, and patients who have diarrhea or constipation as a major part of their illness may evolve to the opposite bowel habit or develop a pattern in which they alternate between the 2. IBS must never be considered as the explanation for rectal bleeding, bloody diarrhea, weight loss, fever, constitutional symptoms, or anemia, and in the presence of these "alarm" symptoms or signs, organic disease must be excluded using conventional stool tests, endoscopic, and radiologic examinations. For the IBS patient without alarm symptoms, the routine use of these tests is not recommended, although for patients with IBS and diarrhea, serologic testing for celiac sprue may be appropriate and cost-effective.[1,2] Of course, screening tests for colon cancer are recommended for all patients 50 years of age or older, including those with IBS.Colon Ischemia -- Pathophysiology and Clinical PresentationColon ischemia generally presents in individuals older than 55 years, a population considerably older than that typically affected by IBS. The known causes of colon ischemia are many, but in the usual case, no definitive cause is found; most episodes of colon ischemia are thought to be caused by brief periods of localized nonocclusive ischemia. The acute onset of mild, lower abdominal pain accompanied or followed by diarrhea, rectal bleeding, or bloody diarrhea is typical. Most patients with colon ischemia have spontaneous resolution of symptoms within several days. Computed tomography of the abdomen usually shows segmental thickening of the colon, although this is not a specific finding. Colonoscopy, if performed within the first 24-48 hours, usually will show submucosal hemorrhage or edema in a segmental pattern (ischemic colopathy). If the examination is repeated within a few days after the onset of symptoms, it will show the disease process to have evolved into a segmental (ischemic) colitis pattern with ulceration and even pseudopolyp formation, an appearance that may mimic inflammatory bowel disease or infectious colitis; biopsy usually is nonspecific, with only infarction and ghost cells pathognomonic of ischemic injury. In general, mesenteric angiography is not used to evaluate patients suspected of having colon ischemia, because by the time of presentation, colonic blood flow usually has normalized.It is important for primary care practitioners to be aware of colon ischemia because it is a common cause of bloody diarrhea in the elderly and can be seen in patients of all ages, especially those who have a coagulation disorder, systemic illness associated with vasculitis, or those with IBS. Moreover, colon ischemia can mimic or be mimicked by infectious colitis or inflammatory bowel disease. Most patients who develop colon ischemia do well with conservative management. For the patient who continues to have symptoms for more than 2 weeks, referral to a gastroenterologist is recommended because it is likely that these individuals will have a complicated course. Lawrence J. Brandt, MD, Chief of Gastroenterology, Montefiore Medical Center, Bronx, New York; Professor of Medicine and Surgery, Albert Einstein College of Medicine, Bronx, New York http://www.medscape.com/viewarticle/488174 New drugsï¿½and some respectï¿½for IBS http://www.acponline.org/journals/news/sep03/ibs.htm Report on the 5th International Symposium on Functional Gastrointestinal DisordersClick on Titles to View TopicsOutcomes of Pediatric Functional GI Disorders Epidemiology/Genetic/Behavioral Factors Basic Principles -- Brain-Gut Brain Imaging Emerging Techniques to Evaluate and Treat Functional GI and Motility Disorders Clinical Applications of Diagnosis and Treatment Functional GI DisordersGeneral Principles of TreatmentPharmacological Treatment Psychological Treatment http://www.iffgd.org/symposium2003report.html


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## eric (Jul 8, 1999)

Molecular Defect Found for the First Time in IBS Patients http://www.ibsgroup.org/cgi-local/ubbcgi/u...c&f=10&t=000940 FYINew IBS Research and getting a grip on the problem of IBS.-------------------------------------------------------------------------------- FYIPathophysiologyAltered Serotonin Signaling?The pathogenesis of IBS remains obscure, and in particular, an explanation for alternating diarrhea and constipation has been elusive. In arguably one of the most important papers presented during this year's meeting, Moses and colleagues 21 studied potential deregulation of the gut's serotonin transporter in IBS. It is known that serotonin (5-hydroxytryptamine or 5HT) is released from enteroendocrine (or enterochromaffin) cells in response to either chemical or mechanical stimulation of the gut mucosa. Serotonin in turn initiates peristalsis, and then the serotonin released is taken up in health by a highly selective serotonin transporter (SERT). One potential mechanism that could explain altered bowel function in IBS is an abnormality in the serotonin transporter itself. The study authors evaluated this hypothesis in patients with IBS with constipation and IBS with diarrhea compared with patients with ulcerative colitis and healthy controls. They were able to convincing show on blinded review that SERT immunoreactivity was less intense in patients with IBS with constipation and patients with ulcerative colitis. If these findings are indeed correct, they represent a landmark observation. The findings suggest that patients with constipation and IBS may have a reduced capacity to reuptake serotonin, leading to excess free serotonin and then desensitization of these receptors, thus reducing motor function. In contrast, in the setting of diarrhea, serotonin uptake was normal. If the underlying abnormality in serotonin transporter function alternated, then this would in turn explain alternating constipation and diarrhea. These data strongly suggest that IBS is a "real" gut disease and a potential diagnostic disease marker. They also suggest that it is valid to subdivide IBS into constipation and diarrhea symptom subgroups. This study also provides additional rationale for the use of serotonin-modulating agents in IBS and provides a new target for drug modulation. Confirmation of these very exciting initial findings in larger patient samples is awaited with great interest.Ask The Expert.Image of a cadeusus. .General Medical Questions.Q: I have suffered from irritable-bowel syndrome for many years. I get diarrhea. The doctors I've seen have offered little help. Recently, my daughter suggested I try an over-the-counter medicine called "5-Hydroxy-tryptophan," made by a company called Natrol Inc. My daughter says it is a mild antidepressant. It seems to have helped quite a bit, but it also seems to slow me down and make me feel tired. Can you give me any information on this? What is it, exactly, and are there any serious side effects? The only other medicine I take is Synthroid....The Trusted Source..Harold J. DeMonaco, M.S.Harold J. DeMonaco, M.S., is senior analyst, Innovative Diagnostics and Therapeutics, and the chair of the Human Research Committee at the Massachusetts General Hospital. He is author of over 20 publications in the pharmacy and medical literature and routinely reviews manuscript submissions for eight medical journals...June 19, 2001.A:Irritable bowel syndrome is now recognized as a disorder of serotonin activity. Serotonin is a neurotransmitter in the brain that regulates sleep, mood (depression, anxiety), aggression, appetite, temperature, sexual behavior and pain sensation. Serotonin also acts as a neurotransmitter in the gastrointestinal tract.Excessive serotonin activity in the gastrointestinal system (enteric nervous system) is thought to cause the diarrhea of irritable-bowel syndrome. The enteric nervous system detects bowel distension (expansion) on the basis of pressure-sensitive cells in the bowel lumen (opening). Once activated, these pressure-sensitive cells promote the release of serotonin, which in turn promotes both secretory function and peristaltic function (the contractions of the intestines that force the contents outward). At least four serotonergic receptors have been identified to be participants in the secretory and peristaltic response.Patients with diarrhea-predominant IBS may have higher levels of serotonin after eating than do people without the disorder. This recognition led to the development of the first drug used specifically to treat diarrheal symptoms of IBS, alosetron (also known as Lotronex). Alosetron blocked the specific serotonin receptors responsible for recognizing bowel distention. In doing so, it blocked the effects of serotonin and reduced both bowel secretions and peristalsis. Constipation was the most common side effect seen. (Note: Alosetron was removed from the market by the manufacturer after repeated reports of a dangerous condition known as ischemic colitis became known.) Tegaserod (Zelmac) is another drug under development and under review by the U.S. Food and Drug Administration for approval. Tegaserod is indicated for the treatment of constipation-predominant IBS and works to increase enteric nervous system serotonin activity.So, increasing serotonin activity in the enteric nervous system produces increased bowel secretions and peristalsis (and potentially diarrhea), whereas depressing serotonin activity produces reduced secretions and reduce peristalsis (and potentially constipation). Increasing serotonin activity in the brain would increase awareness and, in higher doses, produce anxiety, insomnia and restlessness. So I would have expected exactly the opposite effects of those that you experienced.I am unable to identify any possible drug interactions between 5-HTP and Synthroid (levothyroxine) but the symptoms described suggest a check with your doctor may be in order. Persistent feelings of tiredness and constipation may be signs of an underactive thyroid (hypothyroidism).June 19, 2001 The last was from harvard just for the infoFYILevels of 5-Hydroxytryptamine Increase After Meals in Women With Irritable Bowel SyndromeNEW YORK Reuters Health May 05 - Platelet-depleted plasma 5-hydroxytryptamine 5-HT levels increase after meals in women with diarrhea-predominant irritable bowel syndrome d-IBS whose symptoms increase following food ingestion, according to a report in the May issue of Gut.In small studies, 5-HT concentrations in platelet-poor plasma appear higher in women with d-IBS than in healthy women, the authors explain, suggesting a possible link between 5-HT and postprandial symptom exacerbations or IBS itself.Dr. L. A. Houghton from University Hospital of South Manchester, UK and colleagues assessed 5-HT and 5-HIAA its metabolite concentrations, 5-HT turnover, and platelet 5-HT stores in 39 women with d-IBS and 20 healthy female volunteers before and after a standard carbohydrate meal.Although there was no difference in the ratio of postprandial to fasting 5-HT levels between d-IBS patients and healthy controls, the authors report, d-IBS subjects did have higher postprandial concentrations of 5-HT with earlier peak 5-HT levels than did healthy women.Women with d-IBS who reported symptoms following the meal also tended to have higher 5-HT concentrations and higher peak concentrations than did other women, the report indicates, though there was no difference in the time to peak levels compared with asymptomatic women with d-IBS.Fasting 5-HIAA levels were higher in d-IBS women than in healthy controls, the researchers note, but postprandial concentrations did not differ.Fasting and postprandial 5-HT turnover the ratio of 5-HIAA to 5-HT levels did not differ between healthy controls and women with d-IBS, the results indicate, but d-IBS subjects with postprandial symptoms tended to have a lower 5-HT turnover than did d-IBS women without symptoms.Women with d-IBS had significantly higher platelet 5-HT stores than did healthy women, the investigators find, though levels did not differ between d-IBS patients with and without postprandial symptoms."Our results have shown for the first time that symptom exacerbation following meal ingestion in female subjects with d-IBS is associated with increased levels of plasma 5-HT, together with a reduction in 5-HT turnover," the authors conclude. "In addition, baseline platelet stores of 5-HT are elevated in female subjects with d-IBS compared with healthy subjects, supporting increased exposure of platelets to 5-HT in the systemic circulation.""Platelet 5-HT concentrations may have a potential role to play as a marker in the diagnosis and management of d-IBS," the researchers suggest. "This would be similar to the way glycosylated hemoglobin is used to reflect mean blood glucose concentration over a prolonged time period in patients with diabetes mellitus."The investigators add, "Further studies addressing both mucosal 5-HT concentrations and enteroendocrine cell numbers in subjects with d-IBS, as well as similar studies to the present one conducted in subjects with constipation predominant IBS and assessing the transient relationship between symptoms and the 5-HT system need to be performed."Gut 2003;52:663-670.www.medscape.com/viewarticle/453489This is a lot more info on all of it. http://p072.ezboard.com/firritablebowelsyn...picID=461.topic


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## jjohnson (Apr 29, 2004)

Again, thanks.I do remember the Lawrence Brandt article quite well. And far be it for me to question someone of his credentials, but I do seem to recall that in studies with Lotronex, the majority of people who got IC got it in the first month of treatment, and improved quickly upon cessation of treatment. Somehow the hypothesis that the two may be unrelated seems a little hard to believe (much as I would like to believe it.) Again, not very scientific of me, but as a coincidence it seems a little too fantastic. At any rate, hopefully more time and research will sort this all out.


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## eric (Jul 8, 1999)

FYI"Colon ischemia and irritable bowel syndrome "Am J Gastroenterol. 2004 Jul;99(7):1333-7. Related Articles, Links Risk factors for colon ischemia.Walker AM, Bohn RL, Cali C, Cook SF, Ajene AN, Sands BE.Ingenix Epidemiology, Auburndale, Massachusetts 02466, USA.BACKGROUND: To identify predictors of colon ischemia, we examined demographic and clinical characteristics of patients, as well as their prior health care utilization. METHODS: Using insurance data, we identified 700 persons at least 20-yr old with presumed colon ischemia between 1995 and 1999, and 6,440 controls. Case identification was based on diagnosis and procedure codes in insurance claims for which we used a previously reported, validated algorithm. We ascertained preceding medical diagnoses and the use of drugs and health services from the insurance claims files. RESULTS: Patients with colon ischemia were nearly three times as likely to have IBS than controls. A history of nonspecific colitis, lower gastrointestinal tract hemorrhage, systemic rheumatologic disorders, and ischemic heart disease in the preceding 6 months, and abdominal surgery in the past month were also much more common in colon ischemia cases than controls. Use of a drug to treat diarrhea was strongly associated with risk. The most prevalent risk factor for colon ischemia was the use of drugs with a side effect of constipation, found in one-third of cases and one in nine controls. Cases had seen physicians, particularly gastroenterologists, much more commonly in the preceding 6 months than had controls. CONCLUSIONS: Clinically evident colon ischemia arises preferentially in persons with prior abdominal complaints, many of whom carry a diagnosis of IBS. Drugs that reduce bowel motility may constitute a widespread and potentially avoidable risk factor. The frequency of preceding doctor visits, without a specific diagnosis, suggests that colon ischemia may have a prolonged subacute presentation.PMID: 15233674Am J Gastroenterol. 2004 Mar;99(3):486-91. Related Articles, Links Occurrence of colon ischemia in relation to irritable bowel syndrome.Cole JA, Cook SF, Sands BE, Ajene AN, Miller DP, Walker AM.Ingenix Epidemiology, Newton, Massachusetts 02466, USA.OBJECTIVE: In November 2000, alosetron HCl (Lotronex), a treatment for irritable bowel syndrome (IBS), was removed from the U.S. market in part because of the occurrence of colon ischemia in treated patients. Since the relation between colon ischemia and IBS is poorly understood, we evaluated the incidence of colon ischemia among people with and without IBS. METHODS: Using medical claims data from a large health care organization in the United States, we identified 87,449 people with an IBS diagnosis between January 1995 and December 1999. We calculated age- and sex-specific incidence rates in the general population and in IBS patients. RESULTS: There were 740 cases of colon ischemia during 8.5 million person-years of observation in 5.4 million persons. The crude incidence rate was 42.8 cases per 100,000 person-years for IBS patients. By comparison, the incidence rate was 7.2 per 100,000 person-years in the general population. After adjustment for age, sex, and calendar year, the incidence of colon ischemia in people with IBS was 3.4 times higher than in persons without (95% CI 2.6-4.5). CONCLUSIONS: Rates of colon ischemia among patients carrying a diagnosis of IBS are substantially higher than in the general population. Colon ischemia, though unusual in IBS patients, may nonetheless constitute a distinct part of the IBS natural history. Alternatively, it may be a consequence of therapy, or a manifestation of other bowel pathology that is sometimes confused with IBS.PMID: 15056090Am J Gastroenterol. 2003 May;98(5):1117-22. Related Articles, Links Incidence of colonic ischemia, hospitalized complications of constipation, and bowel surgery in relation to use of alosetron hydrochloride.Miller DP, Alfredson T, Cook SF, Sands BE, Walker AM.Ingenix, Epidemiology Division, Newton, Massachusetts 02466, USA.OBJECTIVE: Alosetron hydrochloride (Lotronex), a potent selective 5-hydroxytryptamine(3) receptor antagonist, was approved in February, 2000 in the United States for the treatment of diarrhea-predominant irritable bowel syndrome (IBS) in women. Marketing was suspended in November, 2000, after reports of colonic ischemia and serious complications of constipation. We sought to compare the incidence of colonic ischemia, hospitalized complications of constipation, and bowel surgery among alosetron users and a cohort of patients with IBS who did not use alosetron. METHODS: We sought outcomes of colonic ischemia, hospitalized complications of constipation, and bowel surgery in 3,631 Lotronex users and 2,480 comparison IBS subjects using diagnoses, procedures, and drugs recorded in the UnitedHealthcare insurance claims database, and validated these by chart review. The initial assessment was to last for 3 yr beginning with the start of alosetron treatment and was to include 10,000 Lotronex users; however, the observation period ended by December 31, 2000, after suspension of marketing. RESULTS: There were 3631 alosetron users among members of UnitedHealthcare from March through December, 2000, and we identified 2480 comparison IBS-only patients; follow-up time averaged about 5 months in both groups. There were no instances of colonic ischemia in either cohort. Thirty instances of bowel surgery occurred, giving rates of 10.2/1000 person-yr in the alosetron cohort and 11.8/1000 person-yr in the IBS/no alosetron cohort. There were three cases of hospitalized complications of constipation. The incidence rates were essentially the same in alosetron users (1.24/1000 person-yr) and in IBS patients with no alosetron use (0.92/1000 person-yr). CONCLUSIONS: Alosetron users did not differ from IBS patients not using alosetron in the incidence of bowel surgery or hospitalized complications of constipation; there were no cases of colonic ischemia. The statistical upper limit of colonic ischemia rates in alosetron users was 2.28/1000 person-yr. Because of the market withdrawal, the size of the cohort and the duration of follow-up were smaller than originally planned; consequently, the statements about the safety of alosetron were necessarily limited. On June 7, 2002, the Food and Drug Administration approved alosetron for reintroduction in the U.S. market for women with severe diarrhea-related IBS.PMID: 12809837


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## eric (Jul 8, 1999)

FYI"Best Pract Res Clin Gastroenterol. 2004;18 Suppl:91-7. Related Articles, Links IBS: A syndrome or many diseases?Holtmann G.Department of Gastroenterology, Hepatology and General Internal Medicine, Royal Adelaide Hospital,University of Adelaide, North Terrace, South Australia 5000, Adelaide, Australia.Patients with irritable bowel syndrome (IBS) are characterized by a broad spectrum of gastrointestinal (GI) symptoms. These IBS-symptoms and symptoms of other functional GI disorders frequently overlap. Moreover, at least in patients with severe disease manifestations there is a remarkable psychiatric comorbidity. There is a number of abnormalities of GI functions including sensory and motor dysfunction that are believed to play a role for the manifestation of symptoms in patients with these functional gastrointestinal disorders (FGID). Family studies provide strong evidence for a clustering of FGID in families. Furthermore, twin studies clearly demonstrate an increased concordance in monocygotic compared to dicygotic twins. This points towards the role of one or more hereditary factors. Considering sensory and motor function as well as the psychiatric comorbidity, polymorphisms of adrenergic, opioidergic or serotonergic receptors as well as G-protein beta3 (GNB3) subunit gene polymorphism and polymorphisms of 5-HT transporter genes are suitable mechanisms for these abnormalities. Hence acute GI infections with a mucosal inflammation appear to trigger a cascade of events that ultimately results in the manifestation of FGID, it is reasonable to assume that functionally relevant polymorphisms of genes with immunmodulating and/or neuromodulating features (OPRM1, IL-4, IL-4R, TNFalpha) play a role. It has emerged that a number of various factors may contribute to the manifestation of functional GI disorders. The currently symptom based labels for functional GI disorders may be helpful to categorize patients and target therapy. However, various underlying pathophysiologies may cause similar symptom patterns. Thus, it is reasonable to anticipate that IBS will be dissected accordingly and our disease concepts will accept the irritable bowel syndrome as the clinical manifestation of a number of different disorders.PMID: 15588800


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