Alosetron

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Emeran A. Mayer - One of the best experts on this subject based on the ideXlab platform.

  • Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study
    Alimentary pharmacology & therapeutics, 2008
    Co-Authors: Johanna M. Jarcho, Lin Chang, Steve M. Berman, Brandall Y. Suyenobu, M. Mandelkern, Bruce D. Naliboff, Matthew D. Lieberman, V. Z. Ameen, Emeran A. Mayer
    Abstract:

    Aliment Pharmacol Ther 28, 344–352 Summary Background  Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50–70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5-HT3R antagonist Alosetron is correlated with reduced amygdala activity. Aim  To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with Alosetron. Methods  Basal psychological distress and neural activity (15O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of Alosetron treatment. Results  Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre-treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala. Conclusions  Irritable bowel disease symptom improvement with 5-HT3R antagonist Alosetron is related to pre-treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome.

  • Dual role of 5-HT3 receptors in a rat model of delayed stress-induced visceral hyperalgesia.
    Pain, 2007
    Co-Authors: Sylvie Bradesi, Lijun Lao, Peter G. Mclean, Wendy J. Winchester, Kevin Lee, Gareth A. Hicks, Emeran A. Mayer
    Abstract:

    Despite its beneficial effect in IBS patients, the mechanism of action of the 5-HT3 receptor (5-HT3R) antagonist Alosetron is still incompletely understood. We aimed to characterize the effect and site(s) of action in a model of stress-induced sensitization of visceral nociception in rats. Adult male Wistar rats were equipped for recording of visceromotor response (VMR) to phasic colorectal distension (CRD; 10-60 mmHg). VMR to CRD was recorded 24 h after an acute session of water avoidance (WA) stress (post-WA). Baseline and post-WA responses were measured in rats exposed to WA or sham-WA, treated with Alosetron at 0.3 mg/kg subcutaneously (s.c.) 25 nmol intrathecally (i.t.) or vehicle before post-WA CRD. Some rats were treated with capsaicin/vehicle on the cervical vagus nerve and received Alosetron (0.3 mg/kg, s.c.) 15 min before post-WA CRD. WA stress led to visceral hyperalgesia 24 h later. Alosetron (0.3 mg/kg, s.c.), failed to inhibit WA-induced exacerbation of VMR to CRD. Stress-induced visceral hyperalgesia was abolished when Alosetron was injected intrathecally (P

  • A dose-ranging, phase II study of the efficacy and safety of Alosetron in men with diarrhea-predominant IBS
    The American journal of gastroenterology, 2005
    Co-Authors: Lin Chang, Vanessa Z. Ameen, David J. Mcsorley, George E. Dukes, Eric G. Carter, Emeran A. Mayer
    Abstract:

    A Dose-Ranging, Phase II Study of the Efficacy and Safety of Alosetron in Men with Diarrhea-Predominant IBS

  • Alosetron and irritable bowel syndrome.
    Expert opinion on pharmacotherapy, 2003
    Co-Authors: Emeran A. Mayer, Sylvie Bradesi
    Abstract:

    Alosetron (Lotronex, GlaxoSmithKline) is a potent and selective 5-HT(3)-receptor antagonist approved by the FDA for the treatment of women with diarrhoea-predominant irritable bowel syndrome (IBS) in whom conventional therapy has failed. Studies involving healthy volunteers and IBS patients have demonstrated a beneficial effect of treatment with Alosetron on global IBS symptoms, abdominal pain and discomfort, altered bowel function as well as improvement of quality of life (QOL). Data from animals studies suggest the involvement of 5-HT(3) receptors on intrinsic primary afferent neurons in the mediation of the effect of Alosetron on gastrointestinal motility and secretion. While definitive proof of a visceroanalgesic action is not available, an additional central mechanism of action is suggested by findings obtained in animal models, as well as from human brain imaging studies. Alosetron shows a greater effectiveness in women, and the role of genetic factors underlying inter-individual differences in the response to Alosetron is currently under investigation. The most frequent adverse event associated with the use of Alosetron is constipation and in some rare cases, the development of colonic mucosal ischaemia. In the following review, the most recent reported effects of Alosetron on gastrointestinal motility, visceral sensitivity and anxiety, both in terms of preclinical and clinical data will be discussed. The impact of Alosetron on QOL in IBS patients and the safety of treatment with Alosetron, will also be covered.

  • The effect of the 5-HT3 receptor antagonist, Alosetron, on brain responses to visceral stimulation in irritable bowel syndrome patients.
    Alimentary pharmacology & therapeutics, 2002
    Co-Authors: Emeran A. Mayer, Lin Chang, Steve M. Berman, Stuart W. G. Derbyshire, Brandall Y. Suyenobu, Leah Fitzgerald, M. Mandelkern, Lynn R. Hamm, Brent Vogt, Bruce D. Naliboff
    Abstract:

    SUMMARY Aim: To conduct a placebo-controlled functional brain imaging study to assess the effect of the 5-hydroxytryptamine-3 receptor antagonist, Alosetron, on irritable bowel syndrome symptoms, regional brain activation by rectosigmoid distension and associated perceptual and emotional responses. Methods: Fifty-two non-constipated irritable bowel syndrome patients (28 female) were enrolled in a randomized, placebo-controlled trial with Alosetron (1–4 mg b.d.). Thirty-seven patients completed both brain scans following randomization. Rectosigmoid stimulation was performed with a computer-controlled barostat. Changes in regional cerebral blood flow were assessed using H 15 O positron emission tomography. Stimulus ratings and changes in gastrointestinal symptoms were assessed using verbal descriptor scales. Results: Alosetron, but not placebo, treatment was associated with a decrease in symptom ratings, and reductions in emotional stimulus ratings. Compared to baseline, Alosetron treatment was associated with reduced regional cerebral blood flow in bilateral frontotemporal and various limbic structures, including the amygdala. Compared to placebo, decreases in activity of the amygdala, ventral striatum, hypothalamus and infragenual cingulate gyrus were significantly greater after Alosetron. Conclusions: In non-constipated irritable bowel syndrome patients, 3 weeks of treatment with a 5-hydroxytryptamine-3 receptor antagonist decreases brain activity in response to unanticipated, anticipated and delivered aversive rectal stimuli in structures of the emotional motor system, and this is associated with a decrease in gastrointestinal symptoms.

Eric G. Carter - One of the best experts on this subject based on the ideXlab platform.

  • A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg Alosetron in women with severe diarrhea-predominant IBS.
    The American journal of gastroenterology, 2007
    Co-Authors: Richard Krause, Vanessa Z. Ameen, Amy T Heath, Susan H. Gordon, Marquita A. West, T. Perschy, Eric G. Carter
    Abstract:

    A Randomized, Double-Blind, Placebo-Controlled Study to Assess Efficacy and Safety of 0.5 mg and 1 mg Alosetron in Women With Severe Diarrhea-predominant IBS

  • A dose-ranging, phase II study of the efficacy and safety of Alosetron in men with diarrhea-predominant IBS
    The American journal of gastroenterology, 2005
    Co-Authors: Lin Chang, Vanessa Z. Ameen, David J. Mcsorley, George E. Dukes, Eric G. Carter, Emeran A. Mayer
    Abstract:

    A Dose-Ranging, Phase II Study of the Efficacy and Safety of Alosetron in Men with Diarrhea-Predominant IBS

  • Effect of Alosetron on bowel urgency and global symptoms in women with severe, diarrhea-predominant irritable bowel syndrome: analysis of two controlled trials.
    Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2004
    Co-Authors: Anthony Lembo, Vanessa Z. Ameen, Amy T Heath, Kevin W. Olden, Susan Gordon, Eric G. Carter
    Abstract:

    Abstract Background & Aims : The aim of this study was to assess the effect of Alosetron on bowel urgency and irritable bowel syndrome (IBS) global improvement in diarrhea-predominant IBS (D-IBS). Methods : Women with a lack of satisfactory bowel urgency control at least 50% of the time during screening were randomized to receive Alosetron 1 mg (n = 246) or placebo (n = 246) twice daily. The primary end point was the percentage of days with satisfactory control of bowel urgency. The response rate for the IBS global improvement scale (GIS) was a secondary end point. GIS responders were patients who recorded either moderate or substantial improvement in IBS symptoms relative to the way they felt before entering the study. Other end points included improvement in stool frequency, stool consistency, and percentage of days with incomplete evacuation. Further analyses were performed on a subset of patients who had at least 10 of 14 days during screening (≥71% of days) with a lack of satisfactory control of bowel urgency. Results : Patients had severe chronic IBS symptoms, and 89% of patients had D-IBS. Alosetron resulted in a greater percentage of days with satisfactory control of urgency compared with placebo (69% vs. 56%, respectively, P Conclusions : Alosetron effectively manages bowel urgency and improves global symptoms in women with severe chronic D-IBS.

  • Long-term safety and efficacy of Alosetron in women with severe diarrhea-predominant irritable bowel syndrome.
    The American journal of gastroenterology, 2004
    Co-Authors: William D. Chey, William Y. Chey, Amy T Heath, George E. Dukes, Eric G. Carter, Northcutt Allison Ruth, Vanessa Z. Ameen
    Abstract:

    Long-Term Safety and Efficacy of Alosetron in Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome

  • Original contributionPatient satisfaction with Alosetron for the treatment of women with diarrhea-predominant irritable bowel syndrome
    The American Journal of Gastroenterology, 2002
    Co-Authors: Kevin W. Olden, Ronald G Degarmo, Priti Jhingran, Barbara Bagby, C Decker, Michael Markowitz, Eric G. Carter
    Abstract:

    OBJECTIVE: The efficacy and tolerability of Alosetron in women with diarrhea-predominant irritable bowel syndrome (IBS) have been established in double-blind, placebo-controlled trials. However, the degree to which Alosetron fulfills the needs of those suffering from IBS has not been thoroughly examined from the patient’s perspective. This randomized, double-blind, placebo-controlled study conducted in women with diarrhea-predominant IBS evaluated patients’ overall satisfaction with treatment as well as their satisfaction with respect to several specific medication attributes. METHODS: Patients randomized to receive either Alosetron 1 mg b.i.d. (n = 532) or placebo (n = 269) were administered a questionnaire on which they rated on 7-point Likert scales their prestudy IBS treatment (at the screening visit) or study medication (on wk 12 or final study visit) with respect to overall satisfaction and 11 specific medication attributes. RESULTS: Whereas approximately 10% of patients were satisfied or very satisfied overall with prestudy IBS medication, 69% of patients were satisfied or very satisfied overall with Alosetron and 46% with placebo (p < 0.001) at the end of 12 wk of therapy. The majority of Alosetron-treated patients (61–87%) were satisfied or very satisfied with each of 11 specific medication attributes (p < 0.001 vs placebo for each attribute). Favorable satisfaction ratings for Alosetron were assigned to the five medication attributes that patients considered to be most important, including relief of urgency (68% Alosetron vs 41% placebo), speed of relief (71% vs 40%), time to return to normal activities (75% vs 49%), relief of abdominal pain (62% vs 44%), and prevention of return of urgency (68% vs 42%). CONCLUSIONS: Women with diarrhea-predominant IBS are satisfied with Alosetron 1 mg b.i.d. treatment overall and also with respect to specific attributes of IBS medication they consider most important.

George E. Dukes - One of the best experts on this subject based on the ideXlab platform.

  • A dose-ranging, phase II study of the efficacy and safety of Alosetron in men with diarrhea-predominant IBS
    The American journal of gastroenterology, 2005
    Co-Authors: Lin Chang, Vanessa Z. Ameen, David J. Mcsorley, George E. Dukes, Eric G. Carter, Emeran A. Mayer
    Abstract:

    A Dose-Ranging, Phase II Study of the Efficacy and Safety of Alosetron in Men with Diarrhea-Predominant IBS

  • Long-term safety and efficacy of Alosetron in women with severe diarrhea-predominant irritable bowel syndrome.
    The American journal of gastroenterology, 2004
    Co-Authors: William D. Chey, William Y. Chey, Amy T Heath, George E. Dukes, Eric G. Carter, Northcutt Allison Ruth, Vanessa Z. Ameen
    Abstract:

    Long-Term Safety and Efficacy of Alosetron in Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome

  • a randomized controlled clinical trial of the serotonin type 3 receptor antagonist Alosetron in women with diarrhea predominant irritable bowel syndrome
    JAMA Internal Medicine, 2001
    Co-Authors: Michael Camilleri, Emeran A. Mayer, A.r. Northcutt, William Y. Chey, George E. Dukes, At Heath, David Mcsorley, Allen M Mangel
    Abstract:

    Background Irritable bowel syndrome (IBS) is a common gastrointestinal disorder seen in primary care practice. The symptoms of IBS, including abdominal pain, discomfort, and abnormal bowel function, may be modulated by activity of the serotonin type 3 receptor (5-HT 3 ). The efficacy and tolerability of the 5-HT 3 receptor antagonist Alosetron hydrochloride in nonconstipated female patients with IBS were evaluated in a double-blind, randomized, placebo-controlled trial. Methods Patients received either 1 mg of Alosetron hydrochloride (n = 309) or placebo (n = 317) twice daily for 12 weeks, followed by a 4-week posttreatment period. Adequate relief of IBS pain and discomfort was the primary end point. Secondary end points included improvements in urgency, stool frequency, stool consistency, incomplete evacuation, and bloating. Results Seventy-one percent of patients were classified as having diarrhea-predominant IBS. Forty-three percent of Alosetron-treated patients with diarrhea-predominant IBS reported adequate relief for all 3 months compared with 26% of placebo-treated patients ( P Conclusion Alosetron hydrochloride, 1 mg twice daily for 12 weeks, is effective in relieving pain and some bowel-related symptoms in diarrhea-predominant female patients with IBS.

  • a dose ranging placebo controlled randomized trial of Alosetron in patients with functional dyspepsia
    Alimentary Pharmacology & Therapeutics, 2001
    Co-Authors: Nicholas J Talley, George E. Dukes, S Van Zanten, L R Saez, Teresa B Perschy, Mark R Heath, Christi S Kleoudis, Allen W. Mangel
    Abstract:

    Background: Functional dyspepsia is characterized by upper abdominal pain or discomfort. Aim: To assess the benefit of the 5-HT3-receptor antagonist Alosetron in a pilot, dose-ranging, placebo-controlled, multicentre, randomized clinical trial. Methods: A total of 320 functional dyspepsia patients received placebo (n=81), or Alosetron 0.5 mg b.d. (n=77), 1.0 mg b.d. (n=79) or 2.0 mg b.d. (n=83) for 12 weeks, followed by 1 week of follow-up. Primary efficacy was the 12-week average rate of adequate relief of upper abdominal pain or discomfort. Secondary endpoints assessed pain and upper gastrointestinal symptoms. Results: Twelve-week average rates of adequate relief of pain or discomfort were 46% (95% CI: 37–54%), 55% (95% CI: 46–63%), 55% (95% CI: 47–64%) and 47% (95% CI: 38–55%) in the placebo, 0.5 mg, 1.0 mg and 2.0 mg Alosetron groups, respectively. Alosetron 0.5 mg or 1.0 mg showed potential benefit over placebo for early satiety and postprandial fullness. Females showed greater responses compared to males. Patients with adequate relief had significantly (P < 0.001) greater reductions in severity and frequency of functional dyspepsia symptoms than those without adequate relief. Constipation was the most commonly reported adverse event. Conclusions: Alosetron showed potential benefit in relieving functional dyspepsia symptoms compared to placebo. Patients with adequate relief of upper abdominal pain or discomfort showed improvements in multiple functional dyspepsia symptoms.

  • Tolerability and safety of Alosetron during long-term administration in female and male irritable bowel syndrome patients
    The American journal of gastroenterology, 2001
    Co-Authors: Steven G. Wolfe, William Y. Chey, Mary Kay Washington, Jacqueline P Harding, Amy T Heath, David J. Mcsorley, George E. Dukes, Christine M. Hunt
    Abstract:

    OBJECTIVES: Alosetron (Lotronex) is a new therapeutic agent for irritable bowel syndrome (IBS) in women with diarrhea-predominant IBS. This multicenter randomized, double-blind, placebo-controlled study assessed the safety and tolerability of Alosetron during long-term (≤12 months) treatment. METHODS: A total of 859 subjects (637 female and 222 male) with IBS were enrolled from 130 sites in the United States and were randomized 3:1 to receive 1 mg Alosetron or placebo b.i.d. for 48 wk; of the subjects, 649 (76%) were randomized to the Alosetron group and 212 (24%) to the placebo group. Of the original group, 850 subjects received at least one dose of Alosetron (n = 640) or placebo (n = 210). RESULTS: In all, 59% of the subjects completed the study. Safety data were similar in treatment groups and within age, sex, racial origin, and hormone use. Adverse events were reported by 83% (530/640) and 76% (159/210) of subjects in the Alosetron and placebo groups, respectively, (p < 0.05) and were similar with the exception of constipation; 32% of subjects receiving Alosetron reported constipation, compared to 5% in the placebo group (p < 0.001). Most reports (72%) of constipation were of mild or moderate severity, and 66% of subjects with constipation had single episode of 8 days median duration. Constipation occurred a median of 13 days after initiating treatment and resolved spontaneously, with laxative, or after a brief interruption of therapy. Of the subjects, 4% (11/210) in the Alosetron and 5% (28/640) in the placebo group experienced serious adverse events. Two deaths occurred in subjects with pre-existing cardiovascular risk factors; neither death was attributed to the study drug. CONCLUSIONS: Alosetron 1 mg b.i.d. for 12 months was well tolerated. Constipation is the most frequent adverse event, with a higher incidence of transient constipation in Alosetron-treated patients, typically occurring in the first month of treatment.

Michael Camilleri - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy of Alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials.
    Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 2003
    Co-Authors: Filippo Cremonini, Silvia Delgado-aros, Michael Camilleri
    Abstract:

    The 5HT3 receptor antagonist Alosetron has been tested in several trials on irritable bowel syndrome (IBS) patients. The aim of the present meta-analysis was to determine its effect on adequate relief of pain or global improvement of symptoms in IBS patients. Six large, multicentre, randomized, placebo-controlled trials fulfilled pre-set criteria for high quality and were included in the meta-analysis; 1762 patients were randomized to Alosetron treatment and 1356 to placebo. Seventy-five per cent of the patients experienced diarrhoea-predominant IBS and 93% were females. The pooled odds ratio for adequate relief of pain or global symptoms improvement was 1.81 [95% confidence interval (CI) 1.57-2.10). The average number of patients needed to treat with Alosetron for one patient to achieve improvement over placebo treatment was seven (95% CI 5.74-9.43). The present analysis shows that Alosetron 1 mg b.i.d. positively impacts global symptoms, and pain and discomfort in non-constipated IBS female patients. One in four patients treated with Alosetron may develop constipation. The efficacy of Alosetron is unclear in male patients.

  • Effects of 5‐HT3 antagonism on postprandial gastric volume and symptoms in humans
    Alimentary pharmacology & therapeutics, 2002
    Co-Authors: B. Kuo, Michael Camilleri, D.d. Burton, Blanca E. Viramontes, S. Mckinzie, G. Thomforde, Michael K. O'connor, Benjamin H. Brinkmann
    Abstract:

    Background: Alosetron reduces symptoms of dyspepsia, but the physiological basis for the symptomatic benefit is unclear. Aim: To assess 5-HT3 antagonism on postprandial gastric volume and symptoms after ingestion of maximum tolerable volume of a liquid meal. Methods: In 36 healthy volunteers, we assessed effects of placebo, 0.5 and 1 mg b.d. Alosetron on fasting and postprandial gastric volumes (using single photon emission computed tomography) and symptoms based on 100 mm VAS, 30 min after maximum volume ingested. Results: The 5-HT3 antagonist reduced postprandial symptoms (aggregate score: P 

  • a randomized controlled clinical trial of the serotonin type 3 receptor antagonist Alosetron in women with diarrhea predominant irritable bowel syndrome
    JAMA Internal Medicine, 2001
    Co-Authors: Michael Camilleri, Emeran A. Mayer, A.r. Northcutt, William Y. Chey, George E. Dukes, At Heath, David Mcsorley, Allen M Mangel
    Abstract:

    Background Irritable bowel syndrome (IBS) is a common gastrointestinal disorder seen in primary care practice. The symptoms of IBS, including abdominal pain, discomfort, and abnormal bowel function, may be modulated by activity of the serotonin type 3 receptor (5-HT 3 ). The efficacy and tolerability of the 5-HT 3 receptor antagonist Alosetron hydrochloride in nonconstipated female patients with IBS were evaluated in a double-blind, randomized, placebo-controlled trial. Methods Patients received either 1 mg of Alosetron hydrochloride (n = 309) or placebo (n = 317) twice daily for 12 weeks, followed by a 4-week posttreatment period. Adequate relief of IBS pain and discomfort was the primary end point. Secondary end points included improvements in urgency, stool frequency, stool consistency, incomplete evacuation, and bloating. Results Seventy-one percent of patients were classified as having diarrhea-predominant IBS. Forty-three percent of Alosetron-treated patients with diarrhea-predominant IBS reported adequate relief for all 3 months compared with 26% of placebo-treated patients ( P Conclusion Alosetron hydrochloride, 1 mg twice daily for 12 weeks, is effective in relieving pain and some bowel-related symptoms in diarrhea-predominant female patients with IBS.

  • efficacy and safety of Alosetron in women with irritable bowel syndrome a randomised placebo controlled trial
    The Lancet, 2000
    Co-Authors: Michael Camilleri, David J. Mcsorley, George E. Dukes, Allison R Northcutt, Steven Kong, Allen W. Mangel
    Abstract:

    Summary Background Irritable bowl syndrome (IBS) is a common gastrointestinal disorder with symptoms of abdominal pain, discomfort, and altered bowel function. Antagonists of the type 3 serotonin receptor (5-HT 3 ) have shown promising results in the relief of IBS-associated symptoms. We aimed to confirm these findings by doing a randomised, placebo-controlled trial. Methods We studied 647 female IBS patients with diarrhoea-predominant or alternating bowel patterns (diarrhoea and constipation). 324 patients were assigned 1 mg Alosetron and 323 placebo orally twice daily for 12 weeks, followed by a 4-week post-treatment period. Adequate relief of abdominal pain and discomfort was the primary endpoint; secondary endpoints included improvements in urgency, stool frequency, and stool consistency. Analysis was by intention to treat. Findings 79 (24%) of patients in the Alosetron group and 53 (16%) in the placebo group dropped out. The difference in the drop-out rate between groups was mainly due to a greater occurrence of constipation in the Alosetron group. A greater proportion of Alosetron-treated patients than placebo-treated patients (133 [41%] vs 94 [29%], respectively) reported adequate relief for all 3 months of treatment (difference 12% [4·7–19·2]). Alosetron also significantly decreased urgency and stool frequency, and increased stool firmness. Constipation occurred in 30% and 3% of patients in the Alosetron and placebo groups, respectively. Interpretation Alosetron was well tolerated and clinically effective in alleviating pain and bowel-related symptoms in this population of women with IBS.

  • Effects of Alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome
    Alimentary pharmacology & therapeutics, 2000
    Co-Authors: Miriam Thumshirn, Bernard Coulie, Michael Camilleri, Alan R. Zinsmeister, Duane Burton, C. T. Van Dyke
    Abstract:

    Background: Alosetron, a 5-HT3-receptor antagonist, relieves abdominal pain and improves bowel function in non-constipated, female patients with irritable bowel syndrome. 5-HT3 antagonists delay colonic transit, increase colonic compliance, and increase small intestinal water absorption. Aim: To evaluate the effects of Alosetron on gastrointestinal and colonic transit, rectal compliance and rectal sensation in irritable bowel syndrome. Methods: A double-blind, placebo-controlled, two-dose study of Alosetron was performed in 25 non-constipated irritable bowel syndrome patients, with paired studies before and after 4 weeks of treatment with placebo (n=5), 1 mg Alosetron (n=10) or 4 mg (n=10) Alosetron b.d. Gastrointestinal and colonic transit were measured by scintigraphy. Rectal compliance and sensation were assessed by rectal balloon distention with a barostat. Results: There was a trend (P=0.06) for 1 mg Alosetron to increase rectal compliance (median pressure at half maximum volume 11 mmHg after Alosetron vs. 15.6 mmHg before Alosetron). The 1 mg b.d. Alosetron dose non-significantly retarded proximal colonic transit. Alosetron and placebo reduced sensory scores relative to baseline values; none of the changes induced by Alosetron was significant relative to placebo. Conclusions: Alosetron had no significant effect on gastrointestinal transit or rectal sensory and motor mechanisms in non-constipated irritable bowel syndrome patients in this study. Alosetron’s effects on colonic sensorimotor function and central sensory mechanisms deserve further evaluation.

Lin Chang - One of the best experts on this subject based on the ideXlab platform.

  • Published by Blackwell Publishing Incidence of Ischemic Colitis and Serious Complications of Constipation Among Patients Using Alosetron: Systematic Review of Clinical Trials and Post-Marketing Surveillance Data
    2014
    Co-Authors: Lin Chang, William D. Chey, Christina M. Surawicz, Philip Schoenfeld, Lucinda Harris, Kevin Olden, M. S.
    Abstract:

    BACKGROUND: Ischemic colitis and serious complications of constipation have been reported in association with the use of Alosetron, which is approved for women with severe diarrhea-predominant IBS who have failed conventional therapies. This systematic review calculated the incidence of these adverse events in Alosetron-using patients in clinical trials and post-marketing surveillance. METHODS: A panel of experts in epidemiology and functional bowel disorders reviewed clinical trial report forms and FDA MedWatch forms of each reported case of ischemic colitis or serious complications of constipation. Experts were blinded about whether patients used Alosetron or placebo. Using pre-specified criteria, experts rated the likelihood of an accurate diagnosis and an association between medication use and adverse events. Cases that were not consistent with the reported diagnosis or not possibly associated with medication use were eliminated from calculation of incidence rates of adverse events. RESULTS: Pooled data from clinical trials indicate an increased rate of ischemic colitis among Alosetron-using patients compared to placebo-using patients (0.15 % vs 0.0%, respectively, p = 0.03), but there was no significant difference in the rate of serious complications of constipation. All (19/19

  • An Evidence-Based Look at Misconceptions in the Treatment of Patients with IBS-D.
    Gastroenterology & hepatology, 2013
    Co-Authors: Brian E. Lacy, William D. Chey, Lin Chang
    Abstract:

    Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder and affects up to 12% to 15% of adults in the United States, with a higher prevalence among women and those younger than 50 years. IBS adversely impacts quality of life and medical expenditures, with significant costs arising from healthcare visits and reduced workplace productivity. Recent studies have shown that the adverse effects of IBS are so significant that many patients are willing to accept risks of adverse events from effective treatment to gain symptom relief. Alosetron is a 5-HT3 receptor antagonist approved by the US Food and Drug Administration (FDA) for women with severe diarrhea-predominant IBS that has not responded to traditional therapies. Alosetron yields overall improvements in IBS symptoms in 51% of patients vs 36% treated with placebo, with efficacy continuing undiminished over the course of a 48-week randomized, controlled trial. In real-world clinical practice, patients receiving Alosetron had significant improvements in multiple IBS-related clinical parameters, including the new FDA IBS-diarrhea composite endpoint, lower gastrointestinal symptoms, fecal incontinence, and quality of life. Ischemic colitis and complications of constipation have been rare in occurrence. After nearly a decade of Alosetron use under the risk management plan, adjudication of ischemic colitis and complications of constipation cases indicate that their incidence rates have remained low and stable.

  • Ischemic colitis and complications of constipation associated with the use of Alosetron under a risk management plan: clinical characteristics, outcomes, and incidences.
    The American journal of gastroenterology, 2010
    Co-Authors: Lin Chang, Kenneth Tong, Vanessa Z. Ameen
    Abstract:

    Ischemic Colitis and Complications of Constipation Associated With the Use of Alosetron Under a Risk Management Plan: Clinical Characteristics, Outcomes, and Incidences

  • Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study
    Alimentary pharmacology & therapeutics, 2008
    Co-Authors: Johanna M. Jarcho, Lin Chang, Steve M. Berman, Brandall Y. Suyenobu, M. Mandelkern, Bruce D. Naliboff, Matthew D. Lieberman, V. Z. Ameen, Emeran A. Mayer
    Abstract:

    Aliment Pharmacol Ther 28, 344–352 Summary Background  Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50–70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5-HT3R antagonist Alosetron is correlated with reduced amygdala activity. Aim  To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with Alosetron. Methods  Basal psychological distress and neural activity (15O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of Alosetron treatment. Results  Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre-treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala. Conclusions  Irritable bowel disease symptom improvement with 5-HT3R antagonist Alosetron is related to pre-treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome.

  • Alosetron: an effective treatment for diarrhea-predominant irritable bowel syndrome.
    Women's health (London England), 2007
    Co-Authors: Lucinda A. Harris, Lin Chang
    Abstract:

    Serotonin (5-HT) is one of the key mediators of gut motility, secretion and sensation. Most 5-HT is localized in the gastrointestinal tract. Particularly important for gut function and regulation are the 5-HT1P, 5-HT3 and 5-HT4 receptors. These receptors have been the focus of research evaluating the pathophysiologic mechanisms of irritable bowel syndrome (IBS) as well as targets for the development of novel agents to treat irritable bowel syndrome. Alosetron is one of three 5-HT3 antagonists currently available. The other two, ondansetron and granisetron, are primarily used in the treatment of chemotherapy-induced nausea and vomiting. Alosetron, which slows gut transit, has been approved for the treatment of severe diarrhea-predominant IBS (IBS-D) in women. This review will examine the common, yet therapeutically challenging, disorder IBS, as well as the role of Alosetron in the treatment of IBS-D.