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Safety and tolerability of tegaserod in patients with irritable bowel syndrome and diarrhea symptoms
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2002 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 97, No. 5, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(02)04048-0
Safety and Tolerability of Tegaserod in Patients With Irritable Bowel Syndrome and Diarrhea Symptoms James Fidelholtz, M.D., William Smith, M.D., James Rawls, Pharm.D., Yingqi Shi, Ph.D., Anna Zack, R.Ph., Peter Ru¨egg, M.D., and Martin Lefkowitz, M.D. Regional Research Department, Hightop Medical Research Center, Cincinnati, Ohio; New Orleans Center for Clinical Research, New Orleans, Louisiana; Departments of Clinical Research & Development and Biostatistics, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Department of Clinical Research and Development, Novartis Pharma AG, Basel, Switzerland
OBJECTIVES: Tegaserod is a selective serotonin (5-HT4) receptor partial agonist effective in providing relief from abdominal pain, bloating, and constipation in patients with irritable bowel syndrome. Tegaserod therapy may be associated with early transient diarrhea, which is related to its mechanism of action. This study was performed in patients with irritable bowel syndrome and symptoms of diarrhea to further assess the safety of tegaserod. METHODS: After a 2-wk baseline, patients were randomized (2:2:1) in a double-blind manner to receive 4 mg of tegaserod a day (n ⫽ 35), 12 mg of tegaserod a day (n ⫽ 34), or placebos (n ⫽ 17) for 8 wk. Patients had to fulfill ⱖ2 Rome diarrhea criteria ⱖ25% of the time. Adverse events were recorded. RESULTS: Diarrhea, abdominal pain, headache, flatulence, and fatigue were the most frequently reported adverse events. The frequency rates of diarrhea were 49%, 18%, and 35% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; when the tegaserod data were pooled, the frequency of diarrhea was similar to that of the placebo group (33% and 35%, respectively). No complications of diarrhea (e.g., dehydration and electrolyte abnormalities) were reported. Five patients (6%), all from the tegaserod groups, discontinued study participation because of diarrhea and/or abdominal pain. No serious adverse events were reported. CONCLUSIONS: In this study, tegaserod at doses of 4 and 12 mg/day was safe and not associated with complications of diarrhea or serious adverse events. (Am J Gastroenterol 2002;97:1176 –1181. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Irritable bowel syndrome (IBS) is a common, chronic GI disorder of function affecting approximately 10 –20% of adults in the Western world (1). It is characterized by symptoms of recurrent abdominal pain, bloating, and
changes in bowel function (stool frequency and consistency). Depending on the bowel habit alteration, patients may be grouped according to the predominant symptom: either constipation or diarrhea (2). However, clinical experience of many clinicians indicates that, often, the predominant bowel pattern alternates between constipation and diarrhea over long periods of time (2, 3). The stability of this subgroup classification for an individual patient has not been thoroughly investigated or firmly established. A therapeutic approach to restoring coordinated motility in IBS patients is therefore considered appropriate. The etiology and physiology of the symptoms experienced by patients with IBS, which range in severity from mild to intractable, involve alterations in GI motility, visceral perception, and psychosocial factors (4). The presence of 5-HT receptors throughout the human GI tract (5) and the high amounts of serotonin (5-HT) in enterochromaffin cells and in some enteric nerves (6, 7) suggest that 5-HT plays an important role in several GI functions (8). 5-HT4 receptor agonists have been shown to mediate smooth muscle relaxation (9), enhance the peristaltic reflex (10), lower visceral sensory threshold (11), and stimulate chloride secretion (12). Although these functions have been attributed to the 5-HT4 receptors, a selective 5-HT4 receptor antagonist studied in healthy subjects tended to delay colonic transit but did not affect colonic motor activity or sensory function (13). Tegaserod [HTF 919; 3-(5-methoxy-1H-indole-3-ylmethylene)-N-pentyl-carbazimidamide hydrogen maleate], a new aminoguanidine indole compound, is a selective 5-HT receptor subclass 4 partial agonist (14) that is being developed for the potential treatment of GI disorders (15, 16). The clinical usefulness of tegaserod has been studied primarily in patients with IBS and symptoms of constipation, in whom it has been shown to relieve overall GI symptoms, constipation, and abdominal pain (17–19) and to accelerate orocecal and colonic transit time (20). In some IBS patients, the pattern of bowel movements
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may fluctuate over time between constipation and diarrhea. The primary objective of this study was to assess the safety and tolerability of two dose levels of tegaserod in patients with IBS and symptoms of diarrhea. The results provide safety information for patients with IBS and predominant symptoms of constipation, who may experience occasional periods of diarrhea.
MATERIALS AND METHODS Study Design Outpatients participated in a 10-wk, prospective, multicenter study consisting of a 2-wk placebo-free baseline period plus an 8-wk randomized, double-blind treatment period with placebos or either 4 mg/day or 12 mg/day of tegaserod. Patients received the same dose (either active or placebo) throughout the 8 wk. The tegaserod study medication and placebos were provided as tablets of the same size (6 or 7 mm in diameter) and color. The study medication or a placebo was administered as a twice-daily regimen just before morning and evening meals (double-dummy technique). Concomitant use of loperamide hydrochloride was allowed as a rescue medication (up to a maximum dose of 8 mg/day for no more than 2 days) for bothersome diarrhea (four or more loose or watery bowel movements per day with a sense of urgency for 3 or more consecutive days). Bulk-forming agents (e.g., methylcellulose, psyllium, bran), tricyclic antidepressants, and serotonin reuptake inhibitors (e.g., fluoxetine, sertraline) were also allowed if they had been taken at constant doses for at least 1 month before entry into the study and the dose remained unchanged during the study period. Concomitant use of medications primarily affecting GI motility and/or perception (laxatives, cathartics, prokinetic agents, antidiarrheals, antispasmodic agents, and narcotics) was prohibited. Safety was assessed by monitoring the following variables: adverse events; vital signs; physical examinations; electrocardiogram evaluations; pregnancy screens; laboratory analysis of blood, urine, and stool samples; and daily diaries. Adverse events, including diarrhea, were self-reported by the patients. Daily diary information included records of abdominal discomfort/pain, abdominal bloating, stool consistency, and bowel movements per day. Patients rated their daily symptoms as follows: ●
●
● ●
severity of abdominal discomfort/pain using a 6-point scale (0 ⫽ none, 1 ⫽ very mild, 2 ⫽ mild, 3 ⫽ moderate, 4 ⫽ severe, 5 ⫽ very severe) severity of bloating using a 6-point scale (0 ⫽ none, 1 ⫽ very mild, 2 ⫽ mild, 3 ⫽ moderate, 4 ⫽ severe, 5 ⫽ very severe) number of bowel movements stool consistency using a 7-point scale (1 ⫽ watery, 2 ⫽ loose, 3 ⫽ somewhat loose, 4 ⫽ neither loose nor hard, 5 ⫽ somewhat hard, 6 ⫽ hard, 7 ⫽ very hard)
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Patients One hundred fourteen male and female patients older than 18 yr (no upper age limit) were enrolled and 86 were randomized to receive tegaserod at 4 mg/day (35 patients) or 12 mg/day (34 patients) or placebos (17 patients). Patients were eligible if they were diagnosed with IBS according to the Rome criteria (21) and presented with continuous or recurrent symptoms of at least 3 months duration consisting of abdominal pain or discomfort that was relieved by defecation or associated with a change in the frequency of bowel movements or the consistency of stools. In addition, patients were required to have at least two of the following three symptoms of diarrhea: more than three bowel movements a day, loose or watery stools, or urgency ⬎25% of the time. Patients who had severe diarrhea were not excluded from the study. Organic disease was ruled out by a sigmoidoscopic or colonoscopic examination performed after the appearance of symptoms and within the previous 5 yr. Patients were excluded if they experienced significant changes in bowel habits during the 3 months before screening; if they had non-IBS conditions known to significantly affect bowel transit; if there was evidence of cathartic colon or a history of alcohol, drug, or laxative abuse; or if they intended to take drugs known to affect GI motility and/or sensory perception during the course of the study. Pregnant and breast-feeding women were also excluded, and women of childbearing potential practiced a medically approved method of contraception. The study was approved by institutional review boards and informed consent was obtained from each patient. Data and Statistical Analysis All randomized patients were included in the intent-to-treat population. Background and demographic information (age, sex, weight, race, past/current medical conditions, patient diary data, duration of primary IBS symptoms) were summarized. Safety variables (adverse events, bothersome diarrhea, daily diary measurements, vital signs, electrocardiogram results, clinical laboratory test results, and discontinuations) were summarized.
RESULTS Patients As summarized in Table 1, the patients in this study were predominantly female (67%), although the 4 mg/day group contained a higher proportion of male patients (49%) than the 12 mg/day and placebo groups (18% and 29%, respectively) (p ⫽ 0.02). The patients enrolled were mostly white (88%), with a mean disease duration from 10 to 12 yr. The mean weight was lower in the 12 mg/day group (69 kg) than in the 4 mg/day and placebo groups (82 kg and 84 kg, respectively) (p ⫽ 0.01), which was most likely related to the high percentage of females in this group (82%). The number of bowel movements a week was higher in
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Table 1. Demographics and Baseline Characteristics Category/ Summary Statistics
Demographic Variable Age (yr)
Mean Range Male Female White Black Other No Yes Mean Mean Mean Mean Mean
Sex Race Smoker Weight (kg) Duration of IBS symptoms (yr) Bowel movements/wk Days with four or more bowel movements/wk Median average stool consistency Antidiarrheal use Number of days of antidiarrheal use
Mean
Placebo (N ⫽ 17)
Tegaserod, 4 mg/day (N ⫽ 35)
Tegaserod, 12 mg/day (N ⫽ 34)
48.5 27–67 5 (29.4%) 12 (70.6%) 16 (94.1%) 0 1 (5.9%) 10 (58.8%) 7 (41.2%) 84.3 10.5 19.7 2.3 2.8 3 (17.6%) 0.5
47.3 23–70 17 (48.6%) 18 (51.4%) 31 (88.6%) 1 (2.9%) 3 (8.6%) 28 (80.0%) 7 (20.0%) 82.4 11.5 16.4 1.4 3.1 7 (20.0%) 1.0
41.4 21–77 6 (17.6%) 28 (82.4%) 29 (85.3%) 3 (8.8%) 2 (5.9%) 24 (70.6%) 10 (29.4%) 69.4 9.8 13.2 1.0 3.1 5 (14.7%) 0.6
p 0.08 0.02* 0.88 0.28 0.01* 0.75 0.02* 0.05* 0.26 0.85 0.61
* Statistically significant at the significance level of 0.05.
the placebo group (19.7) than the 4 mg/day and 12 mg/day groups (16.4 and 13.2, respectively) (p ⫽ 0.02). In addition, the number of days with four or more bowel movements per week was higher in the placebo group (2.3) than in the 4 mg/day and 12 mg/day groups (1.4 and 1.0, respectively) (p ⫽ 0.05). The three treatment groups were similar at baseline for median average stool consistency. The mean percentage of patients who used antidiarrheal medication (loperamide) was comparable across the three treatment groups during baseline (20%, 4 mg/day; 15%, 12 mg/day; and 18%, placebo) (p ⫽ 0.85). Futhermore, when the tegaserod data were pooled, rates were similar in tegaserod overall and placebo (17% for tegaserod overall and 18% for placebo). The three treatment groups were also comparable at baseline for the mean number of days of antidiarrheal use (1.0, 4 mg/day; 0.6, 12 mg/day; and 0.5, placebo) (p ⫽ 0.61).
Adverse Events Adverse events were reported by 81% of patients overall. They were more frequent in the tegaserod 4 mg/day (86%) and 12 mg/day (82%) groups than in the placebo group (71%), as presented in Table 2. No serious adverse events occurred. Diarrhea, abdominal pain, headache, flatulence, and fatigue were the most frequently reported adverse events (ⱖ10% occurrence). The frequency rates of diarrhea were 49%, 18%, and 35% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; however, when the tegaserod data were pooled, the frequency of diarrhea was similar to that of the placebo group (33% for tegaserod overall and 35% for placebo). The frequency rates of severe diarrhea were 23%, 12%, and 18% for the 4 mg/day, 12 mg/day, and placebo groups, respectively, and were also similar in tegaserod overall and the placebo group (17% for tegaserod overall and 18% for
Table 2. Frequency of Adverse Events (ⱖ10% in Any Tegaserod Group), Whether or Not Considered Drug Related Nos. of Patients Reporting (%)
Total patients with adverse events p Diarrhea p Abdominal pain p Headache p Flatulence p Fatigue p
Placebo (n ⫽ 17)
Tegaserod, 4 mg/day (n ⫽ 35)
Tegaserod, 12 mg/day (n ⫽ 34)
12 (70.6)
30 (85.7) 0.12 17 (48.6) 0.39 11 (31.4) 0.75 10 (28.6) ⬍0.99 7 (20.0) 0.70 4 (11.4) ⬍0.99
28 (82.4) 0.32 6 (17.7) 0.18 7 (20.6) ⬍0.99 7 (20.6) ⬍0.99 4 (11.8) ⬍0.99 1 (2.9) ⬍0.99
6 (35.3) 4 (23.5) 4 (23.5) 2 (11.8) 1 (5.9)
ps refer to the comparison between the tegaserod dose and placebos.
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Figure 1. Time of onset (days) of the first episode of diarrhea after first intake of study medication.
placebo). There were no statistically significant differences in the frequency rates of diarrhea and severe diarrhea between the tegaserod and placebo groups. No complications related to diarrhea (e.g., dehydration and electrolyte abnormalities) were reported. The first episode of diarrhea occurred within 1–7 days in 23% of patients in the 4 mg/day group versus 15% of patients in the 12 mg/day group and 12% of patients in the placebo group, as shown in Figure 1. Most of the cases of diarrhea were reported as single episodes (4 mg/day, 71%; 12 mg/day, 100%; and placebo, 83%) and did not reoccur during the study. Bothersome diarrhea was defined as four or more loose or watery bowel movements a day for 3 or more consecutive days. There were 17 patients (eight, six, and three patients in the 4 mg/day, 12 mg/day, and placebo groups, respectively) who fulfilled this criteria during the double-blind treatment period. The frequency rates of abdominal pain were 31%, 21%, and 24% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; however, the frequencies were similar when tegaserod overall was compared with placebo (26% for tegaserod overall and 24% for placebo). Severe abdominal pain frequency rates were 9% for both of the tegaserod groups and 12% for the placebo group. There were no statistically significant differences in the frequency rates of abdominal pain and severe abdominal pain between the tegaserod and placebo groups. The mean percentages of patients who used concomitant antidiarrheal medication (loperamide) during the doubleblind treatment period were 31%, 15%, and 24% for the 4 mg/day, 12 mg/day, and placebo groups, respectively (4 mg/day vs placebo, p ⫽ 0.75; 12 mg/day vs placebo, p ⫽ 0.46). Similar to the baseline period, rates were comparable between tegaserod overall and placebo (23% for tegaserod overall and 24% for placebo). The mean numbers of days of antidiarrheal use during the double-blind treatment period were 1.7, 0.2, and 1.1 for the 4 mg/day, 12 mg/day, and placebo groups, respectively (4 mg/day vs placebo, p ⫽ 0.45; 12 mg/day vs placebo, p ⫽ 0.85).
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Figure 2. Mean number of bowel movements per week.
A total of 19 patients (22%) discontinued prematurely. All of these patients were from the tegaserod groups (eight patients in the 4 mg/day group and 11 in the 12 mg/day group). There were 11 discontinuations (13%) (six patients in the 4 mg/day group and five in the 12 mg/day group) related to adverse events. Five patients (6%) (three patients in the 4 mg/day and two in the 12 mg/day group) discontinued study participation because of diarrhea and/or abdominal pain. The remaining six patients discontinued because of adverse events that did not occur in more than one patient (except for headache). Other Safety Assessments Hematology, biochemistry, urinalysis, and vital signs evaluations undertaken during the trial revealed no significant changes from baseline values and no trends or differences between treatment groups. Electrocardiogram evaluation revealed no consistent changes from baseline in mean ventricular rate or PR, QRS, or QTc intervals. Four patients in the 12 mg/day group had nonspecific ST changes. These changes were not considered to be clinically relevant. Bowel Function An increase from baseline in the number of bowel movements (Fig. 2) and the number of days during which patients experienced loose or watery stools (Fig. 3) was observed in both tegaserod groups during the first few weeks of the double-blind treatment period. This tended to decrease over time. No such increase was observed in the placebo group. Similarly, the mean stool consistency score decreased transiently in both tegaserod groups during the first several weeks of treatment (Fig. 4). No such effect was observed in the placebo group. Mean abdominal pain score decreased in all three groups, particularly during the second half of the double-blind treatment period.
DISCUSSION Tegaserod, an aminoguanidine indole, acts as a partial selective agonist at 5-HT4 receptors (14, 15). As a partial
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Figure 3. Mean number of days with loose or watery stools per week.
agonist, tegaserod may be less likely than full agonists to induce receptor downregulation (22). In addition, a partial agonist may act as an antagonist when receptor occupancy with the endogenous ligand (i.e., 5-HT) is high, and as an agonist when receptor occupancy with the endogenous ligand is low (23). Thus, as a partial agonist, tegaserod may provide a balanced modulation of 5-HT4 receptors and normalization of gut activity. Overall, in this study, tegaserod was safe and well tolerated in the 69 outpatients with IBS and symptoms of diarrhea treated with 4 mg/day and 12 mg/day. In concurrence with data from previous studies (20, 24, 25), diarrhea was the most frequently reported adverse event. The highest rates occurred in the 4 mg/day tegaserod group (49%), whereas lower rates were seen in the 12 mg/day group (18%) and placebo group (35%). Although one cannot exclude that 12 mg/day is associated with less diarrhea, pooling of the tegaserod groups shows a rate similar to that of the placebo group (33% vs 35%, respectively). In most cases, diarrhea was reported as an adverse event only once during the study. This finding is consistent with the clinical observation that the diarrhea associated with the use of tegaserod
Figure 4. Mean stool consistency score per week.
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in IBS patients with predominant symptoms of constipation is transient and generally resolves with continued therapy (25). A total of 19 patients discontinued. All of these patients were from the tegaserod groups. Eleven discontinuations were related to adverse events, out of which five were due to diarrhea and/or abdominal pain. Importantly, there were no significant safety problems related to the diarrhea (e.g., volume depletion and electrolyte abnormalities) and there were no serious adverse events reported in this study. An increase in the number of bowel movements and a decrease in stool consistency were observed in the tegaserod groups during the first few weeks of the study; most likely because of the drug’s known promotile activity (16). Of interest, the observed inverse dose-dependent effect on the frequency of adverse events may be related to the partial agonist action of tegaserod or may have been the result of a small sample size and/or the imbalance in the demographics of the treatment groups (three times higher ratio of males in the 4 mg/day group). Tegaserod has been shown in prior studies to accelerate GI transit (20). In this study of patients with IBS and predominant symptoms of diarrhea, adverse event reports of diarrhea were similar in the overall tegaserod groups and the placebo group. However, although this was not interpreted by the patient as diarrhea, the patient diaries did show an increase in bowel movements and looser stools over the first weeks of treatment in the tegaserod groups and not in the placebo group. In addition, discontinuations due to diarrhea were only observed in the tegaserod groups. Thus, the failure to observe a difference in adverse reports of diarrhea likely does not indicate a lack of prokinetic effect of tegaserod. It is also possible that the proximal colon may have accommodated to absorb excess fluid delivered into the right colon secondary to accelerated transit (26). Although overall the data indicate a prokinetic effect of tegaserod in this study, serious adverse events were not observed and significant complications of diarrhea did not occur. In summary, no significant safety problems were observed with the use of tegaserod in patients with IBS and symptoms of diarrhea at doses that have been shown to be effective in IBS patients with symptoms of constipation (4 mg/day and 12 mg/day). Although more patients discontinued treatment in the tegaserod groups than in the placebo group, the incidence rates of diarrhea and abdominal pain were similar in the tegaserod-treated and placebo groups, and no serious adverse events were reported. However, given the relatively small number of patients treated with tegaserod in this study, one must be cautious in extrapolating these findings to the general IBS population of patients with predominant symptoms of diarrhea. The results of this study suggest that tegaserod may be used without any major safety concerns in patients with IBS and predominant symptoms of constipation who occasionally experience episodes of diarrhea as part of the natural course of their IBS.
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ACKNOWLEDGMENT This study was supported by Novartis Pharmaceuticals Corporation. Reprint requests and correspondence: Martin Lefkowitz, M.D., Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936-1080. Received May 2, 2001; accepted Nov. 30, 2001.
REFERENCES 1. Drossman DA, Corazziari E, Talley NJ, et al. Rome II: The functional gastrointestinal disorders, 2nd ed. McLean, VA: Degnon, 2000. 2. Whitehead WE. Patient subgroups in irritable bowel syndrome that can be defined by symptom evaluation and physical examination. Am J Med 1999;107:33– 40. 3. Talley NJ, Zinsmeister AR, Melton J. Irritable bowel syndrome in a community: Symptom subgroups, risk factors, and health care utilization. Am J Epidemiol 1995;142:76 – 83. 4. Mayer EA. Emerging disease model for functional gastrointestinal disorders. Am J Med 1999;107:12S–9S. 5. Ford AP, Clarke DE. The 5-HT4 receptor. Med Res Rev 1993;13:633– 62. 6. Costa M, Brookes SJH. The enteric nervous system. Am J Gastroenterol 1994;89:S129 –37. 7. Gershon M. Roles played by 5-hydroxytryptamine in the physiolgy of the bowel. Aliment Pharmacol Ther 1999;13:15– 30. 8. Talley N. 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: Clinical implications. Aliment Pharmacol Ther 1992;6:273– 89. 9. Prins NH, Van Haselen JF, Lefebvre RA, et al. Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle. Br J Pharmacol 1999;127:1431–7. 10. Grider JR, Foxx-Orenstein AE, Jin J-G. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998;115:370 – 80. 11. Schikowski A, Mathis C, Thewissen M. Dose-dependent modulation of rectal afferent sensitivity by a 5-HT4 receptor agonist. Gastroenterology 1999;116:A643. 12. Budhoo MR, Harris PR, Kellum J. The role of the 5-HT4 receptor in CI- secretion in human jejunal mucosa. Eur J Pharmacol 1996;314:109 –14.
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13. Bharucha AE, Camilleri M, Haydock S, et al. Effects of a serotonin 5-HT4 receptor antagonist SB-207266 on gastrointestinal motor and sensory function in humans. Gut 2000;47: 667–74. 14. Buchheit K-H, Gamse R, Giger R, et al. The serotonin 5-HT4 receptor. 1. Design of a new class of agonists and receptor map of the agonist recognition site. J Med Chem 1995;38:2326 –30. 15. Buchheit K-H, Gamse R, Giger R, et al. The serotonin 5-HT4 receptor. 2. Structure-activity studies of the indole carbazimidamide class of agonists. J Med Chem 1995;38:2331– 8. 16. Pfannkuche H-J, Buhl T, Gamse R, et al. The properties of a new prokinetically active drug: SDZ HTF 919. Neurogastroenterol Motil 1995;7:280. 17. Langaker KJ, Morris D, Pruitt R, et al. The partial 5-HT4 agonist (HTF 919) improves symptoms in constipation-predominant irritable bowel syndrome (C-IBS). Digestion 1998; 59(suppl 3):20. 18. Lefkowitz M, Ruegg P, Dunger-Baldauf C, et al. Validation of a global relief measure in two clinical trials of irritable bowel syndrome (IBS) with tegaserod. Gastroenterology 2000;118: A146. 19. Lefkowitz MP, Ruegg P, Shi Y, et al. Relief of overall gastrointestinal symptoms and abdominal pain and discomfort as outcome measures in a clinical trial of irritable bowel syndrome with tegaserod (HTF 919). Gastroenterology 1999;116: A1027. 20. Prather CM, Camilleri M, Zinsmeister AR, et al. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000; 118:463– 8. 21. Drossman DA, Thompson WG, Talley NJ, et al. Identification of sub-groups of functional gastrointestinal disorders. Gastroenterol Int 1990;3:159 –72. 22. Camilleri M. Tegaserod. Aliment Pharmacol Ther 2001;15: 277–90. 23. Clark RB, Knoll BJ, Barber R. Partial agonists and G proteincoupled receptor desensitization. Trends Pharmacol Sci 1999; 20:279 – 86. 24. Appel-Dingemanse S, Kumle A, Hubert M, et al. First pharmacokinetic-pharmacodynamic study in humans with a selective 5-hydroxytryptamine4 receptor agonist. J Clin Pharmacol 1997;37:229 –37. 25. Mu¨ ller-Lissner SA, Fumagalli I, Bardhan KD, et al. Tegaserod, 5-HT4 receptor partial agonist, relieves abdominal pain and improves bowel function in irritable bowel syndrome. Aliment Pharmacol Ther 2001;15:1655– 66. 26. Debongnie JC, Phillips SF. Capacity of the human colon to absorb fluid. Gastroenterology 1978;74:698 –703.
Vol. 97, No. 5, 2002 ISSN 0002-9270/02/$22.00 PII S0002-9270(02)04048-0
Safety and Tolerability of Tegaserod in Patients With Irritable Bowel Syndrome and Diarrhea Symptoms James Fidelholtz, M.D., William Smith, M.D., James Rawls, Pharm.D., Yingqi Shi, Ph.D., Anna Zack, R.Ph., Peter Ru¨egg, M.D., and Martin Lefkowitz, M.D. Regional Research Department, Hightop Medical Research Center, Cincinnati, Ohio; New Orleans Center for Clinical Research, New Orleans, Louisiana; Departments of Clinical Research & Development and Biostatistics, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; and Department of Clinical Research and Development, Novartis Pharma AG, Basel, Switzerland
OBJECTIVES: Tegaserod is a selective serotonin (5-HT4) receptor partial agonist effective in providing relief from abdominal pain, bloating, and constipation in patients with irritable bowel syndrome. Tegaserod therapy may be associated with early transient diarrhea, which is related to its mechanism of action. This study was performed in patients with irritable bowel syndrome and symptoms of diarrhea to further assess the safety of tegaserod. METHODS: After a 2-wk baseline, patients were randomized (2:2:1) in a double-blind manner to receive 4 mg of tegaserod a day (n ⫽ 35), 12 mg of tegaserod a day (n ⫽ 34), or placebos (n ⫽ 17) for 8 wk. Patients had to fulfill ⱖ2 Rome diarrhea criteria ⱖ25% of the time. Adverse events were recorded. RESULTS: Diarrhea, abdominal pain, headache, flatulence, and fatigue were the most frequently reported adverse events. The frequency rates of diarrhea were 49%, 18%, and 35% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; when the tegaserod data were pooled, the frequency of diarrhea was similar to that of the placebo group (33% and 35%, respectively). No complications of diarrhea (e.g., dehydration and electrolyte abnormalities) were reported. Five patients (6%), all from the tegaserod groups, discontinued study participation because of diarrhea and/or abdominal pain. No serious adverse events were reported. CONCLUSIONS: In this study, tegaserod at doses of 4 and 12 mg/day was safe and not associated with complications of diarrhea or serious adverse events. (Am J Gastroenterol 2002;97:1176 –1181. © 2002 by Am. Coll. of Gastroenterology)
INTRODUCTION Irritable bowel syndrome (IBS) is a common, chronic GI disorder of function affecting approximately 10 –20% of adults in the Western world (1). It is characterized by symptoms of recurrent abdominal pain, bloating, and
changes in bowel function (stool frequency and consistency). Depending on the bowel habit alteration, patients may be grouped according to the predominant symptom: either constipation or diarrhea (2). However, clinical experience of many clinicians indicates that, often, the predominant bowel pattern alternates between constipation and diarrhea over long periods of time (2, 3). The stability of this subgroup classification for an individual patient has not been thoroughly investigated or firmly established. A therapeutic approach to restoring coordinated motility in IBS patients is therefore considered appropriate. The etiology and physiology of the symptoms experienced by patients with IBS, which range in severity from mild to intractable, involve alterations in GI motility, visceral perception, and psychosocial factors (4). The presence of 5-HT receptors throughout the human GI tract (5) and the high amounts of serotonin (5-HT) in enterochromaffin cells and in some enteric nerves (6, 7) suggest that 5-HT plays an important role in several GI functions (8). 5-HT4 receptor agonists have been shown to mediate smooth muscle relaxation (9), enhance the peristaltic reflex (10), lower visceral sensory threshold (11), and stimulate chloride secretion (12). Although these functions have been attributed to the 5-HT4 receptors, a selective 5-HT4 receptor antagonist studied in healthy subjects tended to delay colonic transit but did not affect colonic motor activity or sensory function (13). Tegaserod [HTF 919; 3-(5-methoxy-1H-indole-3-ylmethylene)-N-pentyl-carbazimidamide hydrogen maleate], a new aminoguanidine indole compound, is a selective 5-HT receptor subclass 4 partial agonist (14) that is being developed for the potential treatment of GI disorders (15, 16). The clinical usefulness of tegaserod has been studied primarily in patients with IBS and symptoms of constipation, in whom it has been shown to relieve overall GI symptoms, constipation, and abdominal pain (17–19) and to accelerate orocecal and colonic transit time (20). In some IBS patients, the pattern of bowel movements
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may fluctuate over time between constipation and diarrhea. The primary objective of this study was to assess the safety and tolerability of two dose levels of tegaserod in patients with IBS and symptoms of diarrhea. The results provide safety information for patients with IBS and predominant symptoms of constipation, who may experience occasional periods of diarrhea.
MATERIALS AND METHODS Study Design Outpatients participated in a 10-wk, prospective, multicenter study consisting of a 2-wk placebo-free baseline period plus an 8-wk randomized, double-blind treatment period with placebos or either 4 mg/day or 12 mg/day of tegaserod. Patients received the same dose (either active or placebo) throughout the 8 wk. The tegaserod study medication and placebos were provided as tablets of the same size (6 or 7 mm in diameter) and color. The study medication or a placebo was administered as a twice-daily regimen just before morning and evening meals (double-dummy technique). Concomitant use of loperamide hydrochloride was allowed as a rescue medication (up to a maximum dose of 8 mg/day for no more than 2 days) for bothersome diarrhea (four or more loose or watery bowel movements per day with a sense of urgency for 3 or more consecutive days). Bulk-forming agents (e.g., methylcellulose, psyllium, bran), tricyclic antidepressants, and serotonin reuptake inhibitors (e.g., fluoxetine, sertraline) were also allowed if they had been taken at constant doses for at least 1 month before entry into the study and the dose remained unchanged during the study period. Concomitant use of medications primarily affecting GI motility and/or perception (laxatives, cathartics, prokinetic agents, antidiarrheals, antispasmodic agents, and narcotics) was prohibited. Safety was assessed by monitoring the following variables: adverse events; vital signs; physical examinations; electrocardiogram evaluations; pregnancy screens; laboratory analysis of blood, urine, and stool samples; and daily diaries. Adverse events, including diarrhea, were self-reported by the patients. Daily diary information included records of abdominal discomfort/pain, abdominal bloating, stool consistency, and bowel movements per day. Patients rated their daily symptoms as follows: ●
●
● ●
severity of abdominal discomfort/pain using a 6-point scale (0 ⫽ none, 1 ⫽ very mild, 2 ⫽ mild, 3 ⫽ moderate, 4 ⫽ severe, 5 ⫽ very severe) severity of bloating using a 6-point scale (0 ⫽ none, 1 ⫽ very mild, 2 ⫽ mild, 3 ⫽ moderate, 4 ⫽ severe, 5 ⫽ very severe) number of bowel movements stool consistency using a 7-point scale (1 ⫽ watery, 2 ⫽ loose, 3 ⫽ somewhat loose, 4 ⫽ neither loose nor hard, 5 ⫽ somewhat hard, 6 ⫽ hard, 7 ⫽ very hard)
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Patients One hundred fourteen male and female patients older than 18 yr (no upper age limit) were enrolled and 86 were randomized to receive tegaserod at 4 mg/day (35 patients) or 12 mg/day (34 patients) or placebos (17 patients). Patients were eligible if they were diagnosed with IBS according to the Rome criteria (21) and presented with continuous or recurrent symptoms of at least 3 months duration consisting of abdominal pain or discomfort that was relieved by defecation or associated with a change in the frequency of bowel movements or the consistency of stools. In addition, patients were required to have at least two of the following three symptoms of diarrhea: more than three bowel movements a day, loose or watery stools, or urgency ⬎25% of the time. Patients who had severe diarrhea were not excluded from the study. Organic disease was ruled out by a sigmoidoscopic or colonoscopic examination performed after the appearance of symptoms and within the previous 5 yr. Patients were excluded if they experienced significant changes in bowel habits during the 3 months before screening; if they had non-IBS conditions known to significantly affect bowel transit; if there was evidence of cathartic colon or a history of alcohol, drug, or laxative abuse; or if they intended to take drugs known to affect GI motility and/or sensory perception during the course of the study. Pregnant and breast-feeding women were also excluded, and women of childbearing potential practiced a medically approved method of contraception. The study was approved by institutional review boards and informed consent was obtained from each patient. Data and Statistical Analysis All randomized patients were included in the intent-to-treat population. Background and demographic information (age, sex, weight, race, past/current medical conditions, patient diary data, duration of primary IBS symptoms) were summarized. Safety variables (adverse events, bothersome diarrhea, daily diary measurements, vital signs, electrocardiogram results, clinical laboratory test results, and discontinuations) were summarized.
RESULTS Patients As summarized in Table 1, the patients in this study were predominantly female (67%), although the 4 mg/day group contained a higher proportion of male patients (49%) than the 12 mg/day and placebo groups (18% and 29%, respectively) (p ⫽ 0.02). The patients enrolled were mostly white (88%), with a mean disease duration from 10 to 12 yr. The mean weight was lower in the 12 mg/day group (69 kg) than in the 4 mg/day and placebo groups (82 kg and 84 kg, respectively) (p ⫽ 0.01), which was most likely related to the high percentage of females in this group (82%). The number of bowel movements a week was higher in
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Table 1. Demographics and Baseline Characteristics Category/ Summary Statistics
Demographic Variable Age (yr)
Mean Range Male Female White Black Other No Yes Mean Mean Mean Mean Mean
Sex Race Smoker Weight (kg) Duration of IBS symptoms (yr) Bowel movements/wk Days with four or more bowel movements/wk Median average stool consistency Antidiarrheal use Number of days of antidiarrheal use
Mean
Placebo (N ⫽ 17)
Tegaserod, 4 mg/day (N ⫽ 35)
Tegaserod, 12 mg/day (N ⫽ 34)
48.5 27–67 5 (29.4%) 12 (70.6%) 16 (94.1%) 0 1 (5.9%) 10 (58.8%) 7 (41.2%) 84.3 10.5 19.7 2.3 2.8 3 (17.6%) 0.5
47.3 23–70 17 (48.6%) 18 (51.4%) 31 (88.6%) 1 (2.9%) 3 (8.6%) 28 (80.0%) 7 (20.0%) 82.4 11.5 16.4 1.4 3.1 7 (20.0%) 1.0
41.4 21–77 6 (17.6%) 28 (82.4%) 29 (85.3%) 3 (8.8%) 2 (5.9%) 24 (70.6%) 10 (29.4%) 69.4 9.8 13.2 1.0 3.1 5 (14.7%) 0.6
p 0.08 0.02* 0.88 0.28 0.01* 0.75 0.02* 0.05* 0.26 0.85 0.61
* Statistically significant at the significance level of 0.05.
the placebo group (19.7) than the 4 mg/day and 12 mg/day groups (16.4 and 13.2, respectively) (p ⫽ 0.02). In addition, the number of days with four or more bowel movements per week was higher in the placebo group (2.3) than in the 4 mg/day and 12 mg/day groups (1.4 and 1.0, respectively) (p ⫽ 0.05). The three treatment groups were similar at baseline for median average stool consistency. The mean percentage of patients who used antidiarrheal medication (loperamide) was comparable across the three treatment groups during baseline (20%, 4 mg/day; 15%, 12 mg/day; and 18%, placebo) (p ⫽ 0.85). Futhermore, when the tegaserod data were pooled, rates were similar in tegaserod overall and placebo (17% for tegaserod overall and 18% for placebo). The three treatment groups were also comparable at baseline for the mean number of days of antidiarrheal use (1.0, 4 mg/day; 0.6, 12 mg/day; and 0.5, placebo) (p ⫽ 0.61).
Adverse Events Adverse events were reported by 81% of patients overall. They were more frequent in the tegaserod 4 mg/day (86%) and 12 mg/day (82%) groups than in the placebo group (71%), as presented in Table 2. No serious adverse events occurred. Diarrhea, abdominal pain, headache, flatulence, and fatigue were the most frequently reported adverse events (ⱖ10% occurrence). The frequency rates of diarrhea were 49%, 18%, and 35% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; however, when the tegaserod data were pooled, the frequency of diarrhea was similar to that of the placebo group (33% for tegaserod overall and 35% for placebo). The frequency rates of severe diarrhea were 23%, 12%, and 18% for the 4 mg/day, 12 mg/day, and placebo groups, respectively, and were also similar in tegaserod overall and the placebo group (17% for tegaserod overall and 18% for
Table 2. Frequency of Adverse Events (ⱖ10% in Any Tegaserod Group), Whether or Not Considered Drug Related Nos. of Patients Reporting (%)
Total patients with adverse events p Diarrhea p Abdominal pain p Headache p Flatulence p Fatigue p
Placebo (n ⫽ 17)
Tegaserod, 4 mg/day (n ⫽ 35)
Tegaserod, 12 mg/day (n ⫽ 34)
12 (70.6)
30 (85.7) 0.12 17 (48.6) 0.39 11 (31.4) 0.75 10 (28.6) ⬍0.99 7 (20.0) 0.70 4 (11.4) ⬍0.99
28 (82.4) 0.32 6 (17.7) 0.18 7 (20.6) ⬍0.99 7 (20.6) ⬍0.99 4 (11.8) ⬍0.99 1 (2.9) ⬍0.99
6 (35.3) 4 (23.5) 4 (23.5) 2 (11.8) 1 (5.9)
ps refer to the comparison between the tegaserod dose and placebos.
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Figure 1. Time of onset (days) of the first episode of diarrhea after first intake of study medication.
placebo). There were no statistically significant differences in the frequency rates of diarrhea and severe diarrhea between the tegaserod and placebo groups. No complications related to diarrhea (e.g., dehydration and electrolyte abnormalities) were reported. The first episode of diarrhea occurred within 1–7 days in 23% of patients in the 4 mg/day group versus 15% of patients in the 12 mg/day group and 12% of patients in the placebo group, as shown in Figure 1. Most of the cases of diarrhea were reported as single episodes (4 mg/day, 71%; 12 mg/day, 100%; and placebo, 83%) and did not reoccur during the study. Bothersome diarrhea was defined as four or more loose or watery bowel movements a day for 3 or more consecutive days. There were 17 patients (eight, six, and three patients in the 4 mg/day, 12 mg/day, and placebo groups, respectively) who fulfilled this criteria during the double-blind treatment period. The frequency rates of abdominal pain were 31%, 21%, and 24% for the 4 mg/day, 12 mg/day, and placebo groups, respectively; however, the frequencies were similar when tegaserod overall was compared with placebo (26% for tegaserod overall and 24% for placebo). Severe abdominal pain frequency rates were 9% for both of the tegaserod groups and 12% for the placebo group. There were no statistically significant differences in the frequency rates of abdominal pain and severe abdominal pain between the tegaserod and placebo groups. The mean percentages of patients who used concomitant antidiarrheal medication (loperamide) during the doubleblind treatment period were 31%, 15%, and 24% for the 4 mg/day, 12 mg/day, and placebo groups, respectively (4 mg/day vs placebo, p ⫽ 0.75; 12 mg/day vs placebo, p ⫽ 0.46). Similar to the baseline period, rates were comparable between tegaserod overall and placebo (23% for tegaserod overall and 24% for placebo). The mean numbers of days of antidiarrheal use during the double-blind treatment period were 1.7, 0.2, and 1.1 for the 4 mg/day, 12 mg/day, and placebo groups, respectively (4 mg/day vs placebo, p ⫽ 0.45; 12 mg/day vs placebo, p ⫽ 0.85).
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Figure 2. Mean number of bowel movements per week.
A total of 19 patients (22%) discontinued prematurely. All of these patients were from the tegaserod groups (eight patients in the 4 mg/day group and 11 in the 12 mg/day group). There were 11 discontinuations (13%) (six patients in the 4 mg/day group and five in the 12 mg/day group) related to adverse events. Five patients (6%) (three patients in the 4 mg/day and two in the 12 mg/day group) discontinued study participation because of diarrhea and/or abdominal pain. The remaining six patients discontinued because of adverse events that did not occur in more than one patient (except for headache). Other Safety Assessments Hematology, biochemistry, urinalysis, and vital signs evaluations undertaken during the trial revealed no significant changes from baseline values and no trends or differences between treatment groups. Electrocardiogram evaluation revealed no consistent changes from baseline in mean ventricular rate or PR, QRS, or QTc intervals. Four patients in the 12 mg/day group had nonspecific ST changes. These changes were not considered to be clinically relevant. Bowel Function An increase from baseline in the number of bowel movements (Fig. 2) and the number of days during which patients experienced loose or watery stools (Fig. 3) was observed in both tegaserod groups during the first few weeks of the double-blind treatment period. This tended to decrease over time. No such increase was observed in the placebo group. Similarly, the mean stool consistency score decreased transiently in both tegaserod groups during the first several weeks of treatment (Fig. 4). No such effect was observed in the placebo group. Mean abdominal pain score decreased in all three groups, particularly during the second half of the double-blind treatment period.
DISCUSSION Tegaserod, an aminoguanidine indole, acts as a partial selective agonist at 5-HT4 receptors (14, 15). As a partial
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Figure 3. Mean number of days with loose or watery stools per week.
agonist, tegaserod may be less likely than full agonists to induce receptor downregulation (22). In addition, a partial agonist may act as an antagonist when receptor occupancy with the endogenous ligand (i.e., 5-HT) is high, and as an agonist when receptor occupancy with the endogenous ligand is low (23). Thus, as a partial agonist, tegaserod may provide a balanced modulation of 5-HT4 receptors and normalization of gut activity. Overall, in this study, tegaserod was safe and well tolerated in the 69 outpatients with IBS and symptoms of diarrhea treated with 4 mg/day and 12 mg/day. In concurrence with data from previous studies (20, 24, 25), diarrhea was the most frequently reported adverse event. The highest rates occurred in the 4 mg/day tegaserod group (49%), whereas lower rates were seen in the 12 mg/day group (18%) and placebo group (35%). Although one cannot exclude that 12 mg/day is associated with less diarrhea, pooling of the tegaserod groups shows a rate similar to that of the placebo group (33% vs 35%, respectively). In most cases, diarrhea was reported as an adverse event only once during the study. This finding is consistent with the clinical observation that the diarrhea associated with the use of tegaserod
Figure 4. Mean stool consistency score per week.
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in IBS patients with predominant symptoms of constipation is transient and generally resolves with continued therapy (25). A total of 19 patients discontinued. All of these patients were from the tegaserod groups. Eleven discontinuations were related to adverse events, out of which five were due to diarrhea and/or abdominal pain. Importantly, there were no significant safety problems related to the diarrhea (e.g., volume depletion and electrolyte abnormalities) and there were no serious adverse events reported in this study. An increase in the number of bowel movements and a decrease in stool consistency were observed in the tegaserod groups during the first few weeks of the study; most likely because of the drug’s known promotile activity (16). Of interest, the observed inverse dose-dependent effect on the frequency of adverse events may be related to the partial agonist action of tegaserod or may have been the result of a small sample size and/or the imbalance in the demographics of the treatment groups (three times higher ratio of males in the 4 mg/day group). Tegaserod has been shown in prior studies to accelerate GI transit (20). In this study of patients with IBS and predominant symptoms of diarrhea, adverse event reports of diarrhea were similar in the overall tegaserod groups and the placebo group. However, although this was not interpreted by the patient as diarrhea, the patient diaries did show an increase in bowel movements and looser stools over the first weeks of treatment in the tegaserod groups and not in the placebo group. In addition, discontinuations due to diarrhea were only observed in the tegaserod groups. Thus, the failure to observe a difference in adverse reports of diarrhea likely does not indicate a lack of prokinetic effect of tegaserod. It is also possible that the proximal colon may have accommodated to absorb excess fluid delivered into the right colon secondary to accelerated transit (26). Although overall the data indicate a prokinetic effect of tegaserod in this study, serious adverse events were not observed and significant complications of diarrhea did not occur. In summary, no significant safety problems were observed with the use of tegaserod in patients with IBS and symptoms of diarrhea at doses that have been shown to be effective in IBS patients with symptoms of constipation (4 mg/day and 12 mg/day). Although more patients discontinued treatment in the tegaserod groups than in the placebo group, the incidence rates of diarrhea and abdominal pain were similar in the tegaserod-treated and placebo groups, and no serious adverse events were reported. However, given the relatively small number of patients treated with tegaserod in this study, one must be cautious in extrapolating these findings to the general IBS population of patients with predominant symptoms of diarrhea. The results of this study suggest that tegaserod may be used without any major safety concerns in patients with IBS and predominant symptoms of constipation who occasionally experience episodes of diarrhea as part of the natural course of their IBS.
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ACKNOWLEDGMENT This study was supported by Novartis Pharmaceuticals Corporation. Reprint requests and correspondence: Martin Lefkowitz, M.D., Novartis Pharmaceuticals Corporation, 59 Route 10, East Hanover, NJ 07936-1080. Received May 2, 2001; accepted Nov. 30, 2001.
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