Video/DDW: No Magic Cures for IBS

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Video/DDW: No Magic Cures for IBS

Updated May 5/Index : DDW 2010 Coverage

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This Post Is Not HCV Related/However many people with HCV suffer with IBS.

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NEW ORLEANS -- In this exclusive InFocusâ„¢ report, a prominent researcher in irritable bowel syndrome discusses the challenges for clinicians and patients in managing this heterogeneous condition

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Also View Video @ J & F Blog.

DDW: No Magic Cures for IBS You May Have To Check Back To View DDW VideosIf Videos do not play when selected they will be available for viewing shortly after conclusion(May 6th) of the live coverage. ,

DDW: Novel Agent Cuts Diarrheal IBS

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By Gever, Senior Editor, MedPage TodayPublished: May 05, 2010Reviewed by Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco andDorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

,NEW ORLEANS -- Blocking serotonin synthesis appears to be an effective treatment for diarrhea predominant irritable bowel syndrome (IBS) in some patients, researchers said here.Phase IIa results with LX1031, an oral inhibitor of the enzyme responsible for serotonin production in the intestinal tract, significantly reduced pain and discomfort in patients with diarrheal or mixed IBS, according to Zambrowicz, PhD, of Lexicon Pharmaceuticals, the investigational drug's manufacturer.Zambrowicz, speaking at at Digestive Disease Week, said his study also suggested that urine levels of a serotonin byproduct, 5-HIAA, correlated well with clinical response and could be used to target the drug to those IBS patients most likely to respond to it.Serotonergic pathways are known to play important roles in IBS, whether the condition is diarrheal, constipative, or

mixed.However, several different serotonin receptors, including the 5-HT3 and 5-HT4 subtypes, affect gut motility and IBS symptoms in different ways. That makes it difficult for single agents to achieve just the right mix of effects.Moreover, serotonin and its receptors play important roles in normal physiology throughout the body, researchers noted.Two 5-HT4 agonists that were marketed for constipation-dominant IBS, cisapride (Propulsid) and tegaserod (Zelnorm), had to be pulled from the market when they were found to have caused serious cardiovascular side effects.Even so, Deborah Proctor, MD, a gastroenterologist at Yale University, told MedPage Today that "IBS is serotonin [and] serotonin is IBS."But, she added, "We have to figure out how to make [serotonin-targeting drugs] work for all our patients."LX1031 is intended to avoid the problems discovered with receptor modulators by targeting serotonin

itself in patients with nonconstipating IBS. The theory is that too much serotonin receptor activation is associated with excessive gut motility.The drug inhibits tryptophan hydroxylase, the enzyme that cleaves serotonin from the amino acid tryptophan.Zambrowicz reported partial results from a four-week placebo-controlled trial in 155 patients, about three-quarters of whom had diarrheal IBS.He focused on the correlation between clinical responses and urinary 5-HIAA levels, which were analyzed in half the patients in each group, 76 overall.Efficacy results from the full sample were to be reported here later in another presentation.Two doses of the drug were studied in the trial, 250 and 1,000 mg, as well as placebo, each given four times daily.Patients who reported they had "adequate relief" of pain and discomfort had greater reductions in urinary 5-HIAA levels, according to Zambrowicz.On the final

treatment day, 53% of patients on the high drug dose reported adequate relief in the past week and had mean reductions in 5-HIAA levels of 35%. In the placebo group, 40% of patients reported relief and the mean 5-HIAA reduction was about 2%.The P value for the correlation was 0.027, Zambrowicz reported.A different look at the data indicated that patients who had at least 15% reductions in 5-HIAA levels had less pain and greater global improvement.Among 26 "5-HIAA responders," mean reductions in pain scores on a standard visual analogue scale were about 55% after four weeks, compared with about 30% in 5-HIAA nonresponders.Similarly, patients with at least 15% reductions in urinary 5-HIAA had a mean 125% improvement in global assessments of disease severity versus 40% global improvement in those with smaller 5-HIAA decreases.Zambrowicz told MedPage Today that Lexicon is interested in using 5-HIAA responses to

identify patients most likely to benefit from LX1031 therapy.He said the company also hopes to improve the drug's formulation so that it wouldn't have to be taken more than three times daily.A related compound has also recently shown promise as a treatment for osteoporosis in preclinical models.The study was funded by Lexicon Pharmaceuticals.Zambrowicz was an employee of Lexicon.Proctor reported relationships with Abbott and Genentech.Primary source: Digestive Disease WeekSource reference:Zambrowicz B, et al "Serotonin biomarker levels correlate with clinical response in phase 2 trial of LX1031, a novel serotonin synthesis inhibitor for non-constipating IBS" DDW 2010; Abstract S1053.

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