Effect of tegaserod on colonic transit time in male patients with constipation-predominant irritable bowel syndrome

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1 Blackwell Publishing AsiaMelbourne, AustraliaJGHJournal of Gastroenterology and Hepatology Blackwell Publishing Asia Pty Ltd Original Article Tegaserod and colonic transit K Harish et al. doi:1.1111/j x GASTROENTEROLOGY Effect of tegaserod on colonic transit time in male patients with constipation-predominant irritable bowel syndrome Kareem Harish, Kizhekkan Hazeena, Varghese Thomas, Sunil Kumar, Tony Jose and Puthiyaveetil Narayanan Departments of Gastroenterology and Pharmacology, Calicut Medical College, Calicut, Kerala, India Key words colonic transit time, constipation, irritable bowel syndrome, constipation-predominant, male, tegaserod. Accepted for publication 18 January 26. Correspondence Dr Varghese Thomas, Professor and Head, Department of Gastroenterology, Calicut Medical College, Calicut (Kozhikode) 673 8, Kerala, India. dr_harishk@yahoo.co.in Abstract Background and Aims: Tegaserod is approved for the treatment of constipation-predominant irritable bowel syndrome (C-IBS) in females. The aim of this study was to evaluate the effect of tegaserod on colonic transit time (CTT) and symptoms in male patients with C-IBS. Methods: Forty-four males with C-IBS (Rome II) were enrolled. After a baseline washout period of 2 weeks, 4 patients were randomized to 6 mg twice daily of tegaserod or placebo for 12 weeks. Daily bowel habits and weekly satisfactory relief of symptoms were recorded. Total and segmental CTT were measured using radiopaque markers at baseline and after treatment. Results: The mean ± SD for the total colonic, right colonic, left colonic and rectosigmoid transit time (in hours) were ± 3.92, 7.74 ± 1.55, 5.64 ± 1.51 and 5.58 ± 2.2 in the tegaserod group compared to ± 3.73, 9.69 ± 2.33, 6.6 ± 1.32 and 6.18 ± 2.22 in the placebo group at the end of 12 weeks. There was a statistically significant difference in the total, right and left CTT in the tegaserod group (P <.5) at the end of treatment. Global satisfactory relief at the end of 12 weeks was 75% in the tegaserod group and 5% in the placebo group (P >.5). Greater stool frequency occurred in the tegaserod group (P >.5). There was a significant decrease in the stool consistency at the end of 12 weeks in patients treated with tegaserod (P <.5). Conclusions: Tegaserod causes significant acceleration of CTT in male patients with C- IBS. Although there was a trend towards improvement in bowel symptoms in the treated group, this effect was not statistically significant. Introduction Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders associated with a symptom complex that is characterized by recurrent abdominal pain and/or discomfort, bloating and altered bowel function, which may be either diarrhea or constipation or an erratic bowel habit having features of both. The exact cause and physiology of IBS is not fully understood, but is most likely multifactorial. The proposed pathophysiology includes altered gastrointestinal motility, increased gut sensitivity and psychological factors. 1 Some studies have reported abnormal small bowel and colonic transit time (CTT) correlating with symptoms in IBS but there is a wide interpatient variability. 2 4 Constipation-predominant IBS (C-IBS) tends to have a delayed small bowel and CTT 3 and prokinetic agents are found to be beneficial in these patients. Tegaserod maleate (Zelmac; Novartis Pharma AG, Basel, Switzerland) is an aminoguanidine indole derivative of serotonin that acts as a selective partial agonist at the 5-HT 4 receptor. It has been found to increase gastrointestinal motility in animal models 5,6 and healthy male volunteers. 7 9 Tegaserod has been approved for the treatment of women with C-IBS based on the results of recent clinical trials involving predominantly women It has also been found to be efficacious in relieving symptoms of chronic constipation and has been approved by the Food and Drug Administration (FDA) for the management of chronic constipation in both men and women younger than 65 years based on data from two recent large well designed randomized controlled trials (RCTs). 14,15 Gender and race have no effect on the pharmaco-kinetics of tegaserod. 16 Currently, the efficacy of tegaserod in males with C- IBS remains unknown. As all the studies on the clinical efficacy of tegaserod until now have included women as a majority, it is important to establish if any gender differences exist in the effects of tegaserod on gastrointestinal motility. In a single placebo-controlled trial of 24 women with C-IBS, tegaserod was shown to increase gastrointestinal motility. 17 We hypothesized that tegaserod would accelerate the CTT in males with C-IBS. Thus our primary aim was to determine the Journal of Gastroenterology and Hepatology 22 (27) The Authors 1183

2 Tegaserod and colonic transit K Harish et al. effect of tegaserod on CTT. A secondary aim was to assess the response of tegaserod on the change in bowel function and satisfactory relief of symptoms of IBS in these patients. Method This was a randomized, double blind, placebo-controlled, single center study. After initial screening, all patients entered a 2-week baseline observation period. This was followed by a treatment phase of 12 weeks. The study was conducted between January 24 and June 25. The study protocol was approved by the Human Ethics Committee of our hospital. Patients Male subjects aged 18 years or older who satisfied the Rome II criteria for IBS 18 with the predominant symptom of constipation, defined as presence of two of the three following symptoms for at least 25% of the time during the 3 months prior to the study entry viz: less than three bowel movements per week (not assisted by laxatives or enema), hard/lumpy stools or straining; were screened and enrolled in the study. Patients were excluded from the study if episodes of diarrhea (defined as loose or watery stools and/or more than three bowel movements per day associated with urgency on 25% of days) occurred within the previous 3 months or if they had a history of organic disease of the gastrointestinal tract, severe laxative dependence, regular use of medications that could affect gastrointestinal motility or the presence of any disease which was likely to compromise the patient s ability to complete the study or that would significantly affect bowel motility. Other medications affecting gastrointestinal motility were not permitted during the study. Laxatives were not permitted except as rescue medication. All patients were screened by physical examination, electrocardiogram (ECG), urinalysis, measurement of complete blood count, liver function tests, blood urea, creatinine, thyroid function tests, blood glucose and routine stool tests, and enrolled in the study only if the results were within the normal range. All subjects had an examination of colon (colonoscopy) prior to enrollment in the study. Patients also underwent detailed rectal examination to exclude features of evacuation disorders. All had evidence of normal perineal descent and lack of spasm of puborectalis or anal sphincter. Study design Patients meeting the inclusion criteria underwent a 2-week baseline washout period during which any medications that affect motility were stopped and patients followed their usual diet. During this period all patients recorded their bowel habits daily in a diary. At the end of 2 weeks a CTT using radiopaque markers was obtained. Patients were then randomized using a validated computer system to receive either tegaserod 6 mg orally twice daily or placebo for 12 weeks. Patients were instructed to take the study medication with water within 3 min prior to the morning and evening meal. Throughout the study period, patients were asked to record daily the stool frequency and consistency (1, watery; 2, loose; 3, somewhat loose; 4, neither loose nor hard; 5, somewhat hard; 6, hard; 7, very hard). Patients also assessed their weekly response to treatment by Subjective Global Assessment (SGA) of Relief by answering the following question: Please consider how you felt this past week in regard to your irritable bowel syndrome, in particular, your overall well-being and symptoms of abdominal discomfort, pain and altered bowel habit. Compared to the way you usually felt before entering the study, how would you rate your relief of symptoms during the past week? Possible answers were: completely relieved; considerably relieved; somewhat relieved; unchanged; or worse. At the end of 12 weeks a repeat colonic transit study was performed. All personnel involved in the study remained blinded. Safety was assessed by recording all adverse events and assessment of hematology, blood chemistry parameters, vital signs and physical examinations before and after the double-blind treatment period. Standardization of colonic transit time Twenty uniform radiopaque markers were enclosed in a capsule and ingested by 1 normal subjects at the same time on days 1 3 (, 24 and 48 h) and abdominal X-rays were obtained at 72 h as described. 19,2 However, more than 7% of markers were found to be excreted in all 1 normal healthy subjects. Hence the interval of administering and radiography was reduced to 12 h in the next 1 normal subjects, with which the method could be standardized to calculate CTT. 21 Determination of colonic transit time (total and segmental) Each patient ingested 2 uniform radiopaque markers enclosed in a capsule at, 12 and 24 h (12 h intervals) and an abdominal X-ray was obtained at 36 h. If more than 8% of markers were retained, additional X-rays were obtained at 12-h intervals until at least 8% of the markers had disappeared or a maximum of four X-rays had been obtained. The markers were readily identified and counted on the abdominal film. Localization of markers relied on identification of bony landmarks and gaseous outlines, as originally described by Arhan et al. 22 and validated in subsequent studies using radiopaque markers. 19,2 Markers were judged to be in the anatomic segment based on the gaseous outlines. In the absence of clear outlines of the bowel, markers located to the right of the vertebral spinous processes above a line from the fifth lumbar vertebra to the pelvic outlet were assigned to the right colon. Markers to the left of the vertebral spinous processes and above an imaginary line from the fifth lumbar vertebra to the anterior superior iliac crest were assigned to the left colon. Markers inferior to a line from the pelvic brim on the right and the superior iliac crest on the left were judged to be in the rectosigmoid and rectum. Markers were counted in the right, left and rectosigmoid colons and total and segmental transit times were calculated using the formula: 2 Total colonic transit time (h) = 12/2 ni where ni is the sum of the markers present in the entire X-ray film(s) Segmental colonic transit time (h) = 12/2 ni where ni is total number of markers present in a given film sector (right, left or rectosigmoid) Journal of Gastroenterology and Hepatology 22 (27) The Authors

3 K Harish et al. Tegaserod and colonic transit Statistical analysis The primary end-point evaluated in this study was the CTT, which was compared between treatment groups using an unpaired twosample t-test. Data were expressed as the mean ± standard deviation (SD). Overall assessment of satisfactory relief from IBS symptoms (SGA of Relief) was made at the end of 4 weeks (shortterm response) and at the end of 12 weeks (long-term response). In order to be classified as a responder, patients were to have described at least 75% of their SGA of Relief assessments as either considerably relieved or completely relieved or 1% at least somewhat relieved. The individual bowel function responses (stool frequency, consistency) were also compared among treatment groups. The data for continuous variables were compared using an unpaired two-sample t-test and discrete variables were analyzed using the χ 2 test for significance. P-values of less than.5 were accepted as statistically significant. Results 9.69 ± 2.33, 6.6 ± 1.32 and 6.18 ± 2.22 in the placebo group (Table 2). There was a statistically significant decrease in the mean total, right and left CTT in the tegaserod group at the end of treatment (P <.5). The mean total CTT showed a decrease of 5.6 h in the tegaserod group and 2.67 h in the placebo group compared to baseline (Fig. 2). Satisfactory relief of irritable bowel syndrome symptoms In the first 4 weeks, the mean proportions of patients with satisfactory relief were 5% for tegaserod and 45% for placebo (P =.75). The odds ratio of satisfactory relief were 1.22 (95% confidence interval [CI].29, 5.1). Over 1 12 weeks, the mean proportions of patients with satisfactory relief were 75% for tegaserod and 5% for placebo (P =.1). The odds were 3. (95% CI.66, 14.36). However, the effects of the drug were not statistically significant (P >.5) (Fig. 3). Patient characteristics There were 44 patients who were screened and enrolled. At the end of 2 weeks of the baseline period two patients were excluded because they did not meet the inclusion criteria for C-IBS during the baseline period and another two were excluded because of abnormal laboratory values. Thus, 4 patients who were eligible and randomized completed the study. The data reported are only for the intent-to-treat population. An overview of the trial is illustrated in Figure 1. The baseline demographics of the patients were comparable in both treatment groups (Table 1). Median duration and symptoms of IBS were similar in both groups. 2Patientsdidnot fulfill inclusion/ exclusion criteria 44 Patients with C-IBS enrolled 4 Patients with C- IBS randomised 2Patientshad abnormal baseline laboratory values Effect on colonic transit time The mean total CTT (in hours) at baseline in both groups was similar. The mean ± SD total CTT obtained at the end of the study period was ± 3.92 in the tegaserod group compared to ± 3.73 in the placebo group (P <.5). The mean ± SD segmental CTT (right, left or rectosigmoid) were 7.74 ± 1.55, 5.64 ± 1.51 and 5.58 ± 2.2 in the tegaserod group compared to Tegaserod 6mg bd N=2 Placebo N=2 Figure 1 Patient flow during the study. C-IBS, constipationpredominant irritable bowel syndrome. Table 1 Patient characteristics at baseline Tegaserod n = 22 Placebo n = 22 Age (years) Mean (SD) 28 (8) 27(8) Median Weight (kg) Mean (SD) 59.5 (5.3) 61.75(7.3) Median 59 6 Duration of IBS symptoms (months) Mean (SD) 71.4(29.2) 75 (21.4) Median 6 66 Mean (SD) of number of bowel movements per week 2.55 (.5) 2.8 (.4) Mean (SD) of weekly stool consistency score 5.42 (.71) 5.12 (.93) IBS, irritable bowel syndrome; SD, standard deviation. Journal of Gastroenterology and Hepatology 22 (27) The Authors 1185

4 Tegaserod and colonic transit K Harish et al. Table 2 Colonic transit time at baseline and after treatment in the tegaserod and placebo groups Baseline 12 weeks Tegaserod Placebo Tegaserod Placebo Total transit time ± ± ± ± 3.7 Right colonic transit 1.65 ± ± ± ± 2.3 Left colonic transit 6.69 ± ± ± ± 1.3 Rectosigmoid transit 7.2 ± ± ± ± 2.2 P-values <.5 between groups. All values expressed as mean (in h) +/ standard deviation. Note the significant decrease in the total colonic, right colonic and left colonic transit time in the tegaserod group compared to placebo at the end of the study period. MEAN COLONIC TRANSIT TIME ( hrs ) Before Study After Study Placebo Tegaserod Placebo Tegaserod RESPONDERS (%) P= WEEK (1-4) P=.1 Figure 3 Responder rates for satisfactory relief of irritable bowel syndrome (IBS) symptoms (Subjective Global Assessment of Relief) in the tegaserod and placebo groups. Note that the response rate for overall satisfactory relief is greater in the tegaserod group, most notably the long-term response. The results, however, did not reach statistical significance. (Short-term response viz; week 1 4 P =.75; long-term response viz; week 1 12 P =.1). ( ) Placebo; ( ) Tegaserod WEEK(1-12) Figure 2 Effect of tegaserod on total and segmental colonic transit time (CTT). The total and segmental CTT are similar in both groups prior to study medications. Note the significant decrease in the total colonic, right colonic and left CTT in the tegaserod group compared to placebo at the end of the study period. P <.5 compared to placebo. ( ) Total CTT; ( ) Right CTT; ( ) Left CTT; ( ) Rectosigmoid CTT. Effects on bowel function Baseline stool frequency and consistency were comparable for all subjects. Tegaserod increased the mean stool frequency as early as the end of the first week compared to the placebo group and this difference approached statistical significance (P <.5). Although greater mean stool frequency was reported in the tegaserod group from the second week until the end of the twelfth week, the difference did not reach statistical significance (Fig. 4). There was a decrease in the stool consistency in the tegaserod group and the difference reached statistical significance at the end of the eleventh week and persisted until the end of the study period (Fig. 5). Adverse events There were no major differences in total number and the nature of adverse events reported for the tegaserod group and placebo. No number of bowel movements per week week Figure 4 Effect of tegaserod on weekly bowel movements. There is a significant increase in the number of bowel movements in the tegaserod group compared to placebo at the end of the first week. However, this effect is not persistent throughout the study period. P <.5 compared with placebo. ( ) Tegaserod; ( ) Placebo Journal of Gastroenterology and Hepatology 22 (27) The Authors

5 K Harish et al. Tegaserod and colonic transit mean weekly stool consistency score Figure 5 Effect of tegaserod on weekly stool consistency score. The stool consistency score in the tegaserod group was lower (implying looser stools) compared to placebo and it reached statistical significance at the end of the study period. P <.5 compared with placebo. ( ) Tegaserod; ( ) Placebo. serious drug-related adverse events were reported during the study and no patients discontinued the study after starting the study medication. Discussion week Our study evaluated the effect of tegaserod on CTT in male patients with C-IBS. The data shows that oral tegaserod accelerates the colonic transit in male patients with C-IBS. We observed a statistically significant acceleration of overall colonic transit with 12 weeks of tegaserod therapy and the difference was greatest in ascending colonic transit. These findings probably indicate that the effect of tegaserod is rather more on the proximal part of the colon, which is in agreement with preclinical observations. 5,23 There was also a trend towards an increase in stool frequency in the tegaserod group throughout the study period but it did not reach statistical significance compared to placebo, except at the end of the first week. This was accompanied by an improvement in stool consistency, which reached statistical significance at the end of the study period. Our results showed an advantage for tegaserod in patients overall satisfactory relief from IBS symptoms measured as SGA of Relief, 24 a validated efficacy measure that assesses the impact of treatment on IBS-related symptoms, although this was not statistically significant. A relatively high placebo response is commonly observed in IBS clinical trials (range 84%) 25,26 which is mainly attributed to the fluctuation in severity of the disease over time or the influence of other factors on patients perceptions of relief. Hence a large number of patients are required to assess the impact of treatment on IBS related symptoms in clinical trials. However, our study with a relatively small sample size, was not powered to detect a significant difference for this clinical end-point. However, the effect on CTT need not prove that the drug would be efficacious in the clinical management of males with C-IBS for which further large randomized controlled trials would be required. The radiopaque marker technique is a simple and reliable method for assessing the total and segmental CTT. 2 This method relies on the distribution of ingested radiopaque markers on abdominal radiograph. The projection zones of the right colon, left colon and rectosigmoid are based on bony landmarks and gaseous outlines. 22 The CTT are calculated in each segment (segmental CTT) and through the entire colon (total CTT). This technique of measurement of colonic transit by use of ingested radiopaque markers has been validated and is comparable to the transit time measured with radioisotope studies. 19,2,27 This method is widely followed in various studies as a reliable method of assessment of colonic transit, although there may be difficulties in defining the various segments accurately on the abdominal film and the artificial separation of colonic segments by imaginary lines that connect bony landmarks on the abdominal films may not be always accurate. 21,28,29 However, as our patients had shorter CTT compared to Western populations, 21 we had to reduce the time interval between ingestion of markers to 12 h as compared to 24 h recommended in studies from Western countries. 19,2 So the CTT values obtained from healthy Western populations cannot be applied to our population whose diet and bowel habits are entirely different. Abnormalities in motility and visceral sensation are important in the pathogenesis of symptoms in many IBS patients. 1 A relative decrease in the number of colonic enterochromaffin cells and consequently a lack of serotonin has been implicated in the pathogenesis of patients with chronic constipation. 3 Serotonin appears to be the common link in gastrointestinal motility, intestinal secretion and pain perception and thus it is considered to play an important role in the pathophysiological abnormalities observed in IBS HT 4 receptors are G-coupled proteins that mediate the release of neurotransmitters involved in gastrointestinal motility, such as acetylcholine and calcitonin gene-related peptide. 32,33 5-HT 4 receptor agonism is therefore beneficial for patients with C-IBS because it results in enhanced intestinal motility, increased intestinal secretion and reduced visceral hypersensitivity. 34 Tegaserod, a selective 5-HT 4 receptor agonist, is structurally similar to serotonin. Tegaserod has been shown to trigger peristalsis and to stimulate motility throughout the gastrointestinal tract in various in vitro and in vivo models. 5,6,35 The potential for tegaserod to promote motility in the upper and to a lesser extent lower gastrointestinal tract has been demonstrated in a randomized, placebo-controlled crossover study in 12 healthy men. 9 In a single placebo-controlled trial of women with C-IBS, oral tegaserod 2 mg twice daily administered for 7 days to 24 women had shortened small bowel transit time and to a much lesser extent, the overall CTT. 17 Possible explanations for the lack of a significant improvement in overall CTT with tegaserod in the above study included an inadequate drug dosage and insufficient patient numbers (type II error). The pharmacokinetics of tegaserod are similar in male and female healthy subjects 36 although recent evidence has suggested that sex differences exist among IBS patients in terms of perception, 37 central response to visceral stimuli 38 and colonic transit response to pharmacologic treatment. 39 To the best of our knowledge there is no published report on the effect of tegaserod on colonic motility in males with C-IBS. In summary, tegaserod causes acceleration of overall colonic transit, particularly of ascending colon in males with C-IBS, and this is associated with improved bowel function. Although there was a trend towards improvement of bowel symptoms in the Journal of Gastroenterology and Hepatology 22 (27) The Authors 1187

6 Tegaserod and colonic transit K Harish et al. treated group, it did not reach statistical significance. This may be due to a type II error in this study, owing to the small sample size. Given its effects on colonic transit, it is likely to be useful clinically even in males with C-IBS. It is necessary to conduct further large, randomized controlled trials to assess the clinical efficacy of tegaserod in males with C-IBS. Acknowledgment We would like to thank the staff members of the Department of Gastroenterology, Pharmacology and Statistics for conducting the study and their assistance in the preparation of the manuscript. References 1 Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology 22; 123: McKee DP, Quigley EM. Intestinal motility in irritable bowel syndrome: is IBS a motility disorder? Part 1. Definition of IBS and colonic motility. Dig. Dis. Sci. 1993; 38: Cann PA, Read NW, Brown C, Hobson N, Holdsworth CD. 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7 K Harish et al. Tegaserod and colonic transit 36 Appel-Dingemanse S, Horowitz A, Campestrini J, Osborne S, McLeod J. The pharmacokinetics of the novel promotile drug, tegaserod, are similar in healthy subjects-male and female, elderly and young. Aliment. Pharmacol. Ther. 21; 15: Chang L, Naliboff BD, Schmulson M et al. The role of gender and bowel habit predominance on visceral perception in IBS. Gastroenterology 21; 12: A Naliboff BD, Berman S, Chang L et al. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology 23; 124: Viramontes BE, Camilleri M, McKinzie S et al. Gender-related differences in slowing colonic transit by a 5-HT3 antagonist in subjects with diarrhea predominant irritable bowel syndrome. Am. J. Gastroenterol. 21; 96: Journal of Gastroenterology and Hepatology 22 (27) The Authors 1189