Vanessa Z. Ameen

A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS.

BACKGROUND:A randomized, double blind, placebo-controlled dose-ranging study was conducted to assess the efficacy of alosetron in men with diarrhea-predominant irritable bowel syndrome (IBS).METHODS:Six hundred and sixty-two men were randomized to treatment with alosetron 0.5, 1.0, 2.0, 4.0 mg, or placebo twice daily for 12 wk, followed by a 4-wk posttreatment period. Adequate relief of IBS pain and discomfort during week 5–12 of the treatment phase was the primary endpoint; secondary endpoints included bowel urgency, stool frequency, and consistency, incomplete evacuation, bloating, and abdominal pain or discomfort.RESULTS:Subjects ranked urgency and abdominal pain as their most bothersome IBS symptoms. The average rate of adequate relief during week 5–12 was significantly higher in the alosetron 1.0 mg twice-daily group compared to placebo (53%vs 40%, p= 0.04), and all doses of alosetron significantly reduced stool consistency scores (p < 0.001) indicating firmer stools. No significant effects of alosetron were seen with regard to urgency, number of bowel movements, bloating, and incomplete evacuation. Constipation was the most common adverse event and occurred in a dose-related manner among subjects receiving alosetron, 9% (0.5 mg twice daily), 15% (1.0 mg twice daily), 11% (2.0 mg twice daily), and 21% (4.0 mg twice daily). No serious adverse events of constipation were reported. One subject in the 0.5 mg twice-daily group had an episode of rectal bleeding suggestive of a possible diagnosis of ischemic colitis.CONCLUSION:Alosetron 1 mg twice daily provided adequate relief of IBS pain and discomfort, and improved stool consistency in men with diarrhea-predominant IBS.

Irritable Bowel Syndrome: Toward an Understanding of Severity

Irritable bowel syndrome (IBS) is a chronic disorder with symptoms that range in severity from mild and intermittent to severe and continuous. Although severity is a guiding factor in clinical decision making related to diagnosis and treatment, current guidelines related to IBS do not address the issue of severity. Recent data suggest that severity as a multidimensional concept, not fully explained by intensity of symptoms, has important clinical implications including health care utilization and health-related quality of life. Components of IBS severity include symptom intensity, time of assessment, whether the patient or physician makes the severity determination, the type of scale used to measure severity, and the degree of disability or impairment. Currently no consensus definition of IBS severity exists, although 2 validated scales of IBS severity have recently been published. Review of the literature suggests that the prevalence of severe or very severe IBS is higher than previously estimated with a range from 3%-69%. Individual IBS symptoms are important but are not sufficient to explain severity. Rather, severity has multiple components including health-related quality of life, psychosocial factors, health care utilization behaviors, and burden of illness. However, studies have not been adequately designed to determine the relative values of these factors in IBS severity.

Effect of alosetron on bowel urgency and global symptoms in women with severe, diarrhea-predominant irritable bowel syndrome: Analysis of two controlled trials☆

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 < 0.001). Greater percentages of alosetron-treated patients were GIS responders at 4, 8, and 12 weeks compared with placebo (59% vs. 41%, 63% vs. 41%, and 68% vs. 46%, respectively, P < 0.001). Patients with more frequent urgency had similar results. Constipation occurred in 28% and 9% of subjects in the alosetron- and placebo-treated groups, respectively. No cases of ischemic colitis were reported. CONCLUSIONS Alosetron effectively manages bowel urgency and improves global symptoms in women with severe chronic D-IBS.

Validation of Irritable Bowel Syndrome Global Improvement Scale: An Integrated Symptom End Point for Assessing Treatment Efficacy

The Global Improvement Scale (GIS) assesses multiple irritable bowel syndrome (IBS) symptoms using a patient-defined 7-point Likert scale ranging from symptoms substantially worse to substantially improved. To evaluate the scale as an efficacy end point, data were collected from two 12-week randomized, double-blind, placebo-controlled studies of female nonconstipated IBS patients. GIS responders were defined as having substantial or moderate improvement in IBS symptoms. GIS responders had more days with satisfactory control of urgency, firmer stools, fewer stools per day, and fewer days with incomplete evacuation compared to nonresponders. Substantially more GIS responders (90% and 89% in studies 1 and 2, respectively) were satisfied or very satisfied with their treatment overall compared to nonresponders (13% and 11%) ( r = 0.8 in both studies). GIS responders had greater satisfaction with medication relief of pain and discomfort and the time needed to return to usual activities. Favorable correlations between GIS and work and nonwork productivity losses were observed. Correlation of the GIS measure with IBS clinical end points establishes the validity of the GIS for measuring improvement in IBS symptoms. The GIS may be useful in assessing the efficacy of IBS interventions in future clinical trials.

Pharmacodynamics and pharmacokinetics of oral contraceptives co-administered with alosetron (Lotronex).

The 5-HT3 receptor antagonist alosetron (Lotronex) is indicated for use in women with severe, chronic, diarrhea-predominant irritable bowel syndrome (IBS) who have failed conventional therapy. Oral contraceptives (OCs) and alosetron are potential co-medications in women of childbearing age. This study assessed the effect of alosetron co-administration on pharmacodynamic markers of contraceptive efficacy, on the pharmacokinetics of estrogen and progesterone OC components, and on the activity of biochemical markers for the risk of thrombosis. This was an open label, nonrandomized two-way crossover study in 18 healthy women stabilized for 3 months on a low-dose OC containing ethinyl estradiol (EE) and levonorgestrel (LN). Alosetron had no effect on serum concentrations of luteinizing hormone (LH) or follicle-stimulating hormone. Ovarian activity grades (assessing follicle size, progesterone, and 17β-estradiol concentrations) were similar during OC use with and without alosetron. Steady-state (Day 21) AUC24, Cmax, and tmax of both LN and EE were similar during coadministration of alosetron with an OC. Concentrations and activity of biochemical markers of thrombosis risk were not different in the presence of alosetron. These results indicate that alosetron does not alter the pharmacokinetics or pharmacodynamic markers of efficacy for a low-dose combination OC. The results also suggest that thromboembolic risk is not increased when alosetron is co-administered with an OC.

The Effects of a Short Course of Antibiotics on Alvimopan and Metabolite Pharmacokinetics

Alvimopan is a novel, oral, peripherally acting mu‐opioid receptor (PAM‐OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid‐induced analgesic effects. It is metabolized by gut microflora to an active amide‐hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open‐label, sequential drug interaction study was conducted in 45 participants who received twice‐daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8–99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan Cmax by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.

Characterization of the Inflammatory Response in Idiopathic Gastroparesis Reveals a Role for Macrophage Derived Factors

Abdominal bloating symptoms are highly prevalent in subjects with functional GI disorders and are associated with increased healthcare utilization and reduced quality of life [APT 2010]. Altered intestinal transit and abnormal intraluminal fermentation have been proposed as possible pathophysiological mechanisms for these symptoms. We have previously demonstrated slower colonic transit in subjects with abdominal bloating compared to subjects without bloating. In this study we investigated the hypothesis that abdominal bloating symptoms are associated with abnormally increased intestinal fermentation.Aim: To investigate and compare the magnitude and site of intestinal fermentation in subjects with functional GI symptoms and bloating (FGI-B) and healthy controls (HC) by measuring pH in the GI lumen. Methods: We studied a total of 47 subjects; FGI-B (n=37) and HC (n=10). Intestinal intraluminal pH was used as a surrogate marker for intestinal fermentation. The intestinal pH levels were measured at different segments of the GI tract using a wireless motility capsule (WMC). Comparisons of transit time and pH variables between the groups were done using t-test; correlation analyses were done using Spearman Correlation Coefficients. Results: Intestinal pH levels were significantly lower at the proximal colon (Q1) of subjects with FGI-B compared to HC (mean pH 6.27 vs. 6.84; p=0.008) suggesting a significantly higher intraluminal intestinal fermentation at this segment of the GI tract in these subjects. The mean intraluminal colonic pH levels in the FGI-B group were also lower than that of HC at other segments of the large intestine; however, statistical differences were noticed only in the proximal and total colon. Mean colonic pH levels at the four (proximal to distal) colonic segments and the total colon are provided in the following Table. There were no noticeable differences between the groups in mean pH levels at any of the segments of the small bowel. The average total colonic pH significantly correlated with the total colonic transit time (r=0.34; p=0.014). However, no correlation was found between the average small bowel pH and small bowel transit time.Conclusions: We provide evidence of abnormal intestinal fermentation in subjects with functional GI symptoms and bloating. We demonstrate that bloating symptoms are associated with increased fermentation in the large rather than the small bowel. WMCmay be helpful in identifying underlying physiological abnormalities and guide treatment in patients with bloating symptoms. Mean intraluminal pH levels in subjects with abdominal bloating and healthy controls