Tegaserod for the treatment of constipation-predominant irritable bowel syndrome

Tegaserod, a potent, partial serotonin 4 receptor (5-HT4) agonist, is an effective agent for the treatment of females with constipation-predominant irritable bowel syndrome. Tegaserod enhances gastric motility, stimulates peristaltic reflux and intestinal secretion, inhibits visceral sensitivity, and/or shortens colonic transit time. This agent may help women who have failed to respond to diet and exercise, laxatives, and other forms of therapy. The optimal dose of tegaserod is 6 mg twice daily and results in decreased number of days per month with pain, bloating, and days without bowel movements. Tegaserod is less effective in males than females in the treatment of constipation-predominant irritable bowel syndrome. Tegaserod is well tolerated. Diarrhea is the most frequent adverse effect. The diarrhea tends to occur most frequently during the first few months of therapy and decreases with continued administration.     

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

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, 40 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 18.96 +/- 3.92, 7.74 +/- 1.55, 5.64 +/- 1.51 and 5.58 +/- 2.2 in the tegaserod group compared to 22.47 +/- 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 < 0.05) at the end of treatment. Global satisfactory relief at the end of 12 weeks was 75% in the tegaserod group and 50% in the placebo group (P > 0.05). Greater stool frequency occurred in the tegaserod group (P > 0.05). There was a significant decrease in the stool consistency at the end of 12 weeks in patients treated with tegaserod (P < 0.05). 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.     

Abnormal colonic propagated activity in patients with slow transit constipation and constipation-predominant irritable bowel syndrome

BACKGROUND: The pathophysiological basis of constipation is still unclear, and the role of colonic dysfunction is debated, especially in irritable bowel syndrome. Objective data are quite scarce, especially concerning colonic propulsive activity. AIMS: To evaluate high- and low-amplitude colonic propulsive activity in constipated patients (slow-transit type and irritable bowel syndrome) in comparison with normal controls. PATIENTS AND METHODS: Forty-five constipated patients (35 with slow-transit constipation and 10 with constipation-predominant irritable bowel syndrome) were recruited, and their data compared to those of 18 healthy subjects. Twenty-four-hour colonic manometric recordings were obtained in the three groups of subjects, and data concerning high- and low-amplitude colonic propulsive activity were then compared. RESULTS: High-amplitude propagated contractions were significantly (p < 0.05) decreased in patients with slow-transit constipation and constipation-predominant irritable bowel syndrome with respect to controls (1.5 +/- 0.4, 3.7 +/- 2, and 6 +/- 1 events/subject/day, respectively). In slow-transit constipation, a significant decrease of contractions' amplitude was also observed. Concerning low-amplitude propagated contractions, patients with slow-transit constipation had significantly less events with respect to patients with constipation-predominant irritable bowel syndrome (46 +/- 7 vs. 87.4 +/- 19, p = 0.015); no differences were found between patients with slow-transit constipation and controls and between patients with constipation-predominant irritable bowel syndrome and controls. All three groups displayed a significant increase of low-amplitude propagated contractions after meals (6.3 +/- 2 vs. 18.2 +/- 5 for controls, p < 0.005; 6.4 +/- 1.4 vs. 16.3 +/- 2.4 for slow-transit constipation, p < 0.005; 10.5 +/- 3.2 vs. 32.6 +/- 7 for constipation-predominant irritable bowel syndrome, p = 0.001). CONCLUSIONS: Low-amplitude propagated contractions may represent an important physiologic motor event in constipated patients, reducing the severity of constipation in patients with irritable bowel syndrome and preserving a residual colonic propulsive activity in patients with slow-transit constipation.     

Effect of renzapride on transit in constipation-predominant irritable bowel syndrome.

BACKGROUND & AIMS: The aim of this study was to evaluate the dose-ranging pharmacodynamic effects of renzapride, a 5-hydroxytryptamine 4 (5-HT4) receptor full agonist/5-HT3 receptor antagonist, on gastrointestinal transit and symptoms in patients with constipation-predominant irritable bowel syndrome (C-IBS). METHODS: Forty-eight patients (46 women) with C-IBS underwent recording of baseline symptoms for 1 week. Twelve patients per group were randomized (double-blind, parallel design) to 11-14 days of renzapride (1, 2, or 4 mg) or placebo, once daily. Daily bowel habits and weekly satisfactory relief of IBS symptoms were recorded. At the end of treatment, gastric emptying (GE), small bowel transit (SBT), and colon transit (CT) were measured by scintigraphy. The relationship between CT and bowel function was evaluated. RESULTS: A statistically significant linear dose response to renzapride was detected for CT (GC8 h, P = 0.004; GC24 h, P = 0.056), and ascending colon (AC) emptying t1/2 (P = 0.019), but not for GE (t1/2, P = 0.088; or SBT, P = 0.41). AC half-time transit (t1/2) for placebo and 4 mg of renzapride were (median) 17.5 vs. 5.0 hours, respectively. Improved bowel function scores (stool form and ease of passage, but not frequency) were significantly (P < 0.05) associated with accelerated CT. Pharmacokinetic analysis showed linear kinetics of renzapride with a mean t1/2 in plasma of 10 hours. Bowel function and satisfactory relief were not significantly altered by renzapride, although a type II error cannot be excluded. No significant adverse clinical, laboratory, or electrocardiogram (ECG) effects were observed. CONCLUSIONS: Renzapride causes clinically significant dose-related acceleration of CT, particularly ascending colonic emptying; this acceleration of transit is associated with improvement of bowel function in female C-IBS patients.     

Comparison of colonic transit time between patients with constipation-predominant irritable bowel syndrome and functional constipation

Background/Aim  

Functional constipation (FC) and constipation-predominant IBS (C-IBS) are two main subtypes of constipation. Using radio-opaque markers is an easy and cost effective method to measure colonic transit time (CTT). We designed this study to compare the CTT between these two groups of constipated patients.     

Effect of 5 days linaclotide on transit and bowel function in females with constipation-predominant irritable bowel syndrome

BACKGROUND & AIMS: Oral linaclotide, a novel agonist of guanylate cylase-C, stimulates intestinal fluid secretion and transit, and decreases visceral hypersensitivity in animal studies. In healthy volunteers, linaclotide was safe, well tolerated, increased stool frequency, and decreased stool consistency and time to first bowel movement. This randomized, double-blind, placebo-controlled study evaluated the effects of oral linaclotide, 100 and 1000 microg once daily, in 36 women with constipation-predominant irritable bowel syndrome; colonic transit was normal in >50% patients. METHODS: Participants underwent 5-day baseline and 5-day treatment periods; gastrointestinal transit (by validated scintigraphy) and bowel function (by daily diaries) were assessed. Treatment effects were compared using analysis of covariance (baseline colonic transit as covariate) with pairwise comparisons of each dose vs placebo. RESULTS: There was a significant overall treatment effect on ascending colon emptying half-time (P = .015) and overall colonic transit at 48 hours (P = .02) but not overall transit at 24 hours (P = ns), with a significant acceleration by linaclotide 1000 microg vs placebo (P = .004 and P = .01, respectively) but no significant effect of linaclotide 100-microg dose. There were significant overall treatment effects on stool frequency, stool consistency, ease of passage, and time to first bowel movement with a strong dose response for stool consistency (overall, P < .001). No safety issues were identified. CONCLUSIONS: In women with constipation-predominant irritable bowel syndrome, linaclotide 1000 microg once daily significantly accelerated ascending colonic transit and altered bowel function. Further randomized controlled trials of clinical efficacy of linaclotide are warranted.     

伊托必利治疗功能性消化不良重叠便秘型肠易激综合征疗效观察

目的 观察伊托必利治疗功能性消化不良(FD)重叠便秘型肠易激综合征(C-IBS)患者的疗效.方法 将符合FD标准及重叠C-IBS患者分为FD治疗组(40例)、FD观察组(20例)、FD重叠C-IBS治疗组(40例)和FD重叠C-IBS观察组(20例),FD治疗组和FD重叠C-IBS治疗组均给予伊托必利100 rag/次,每日3次,疗程8周.观察并记录4组患者上腹饱胀、早饱、腹痛等症状及C-IBS患者便秘改善情况.FD治疗组和FD重叠C-IBS治疗组于治疗前及治疗后2周进行胃排空试验.结果 FD治疗组和FD重叠C-IBS治疗组患者腹痛、上腹饱胀、早饱等症状均有不同程度改善,其中FD重叠C-IBS治疗组改善程度更为明显,且排便情况亦有显著改善.B超监测胃排空显示,与观察组相比,FD治疗组和FD重叠C-IBS治疗组患者治疗后胃窦收缩幅度及胃排空时间均有显著改善(P<0.05).结论 伊托必利治疗FD有效,尤其是对FD重叠C-IBS治疗组的疗效优于FD治疗组.     

功能性便秘和便秘型肠易激综合征的结肠运输试验及直肠感觉阈值比较

目的 对功能性便秘和便秘型肠易激综合征（IBS）患者进行肠道转运时间及其肛门直肠运动和直肠容量感觉研究，探讨两类疾病的结肠运动方式有何不同。方法 用不透X线标志物测定全结肠通过时间和结肠分段通过时间并计算转动指数。用电子气压泵研究肛门直肠压力、直肠对容量刺激的感觉和直肠顺应性。结果 便秘型IBS的结肠转动时间延长主要在右半结肠。功能性便秘的各个节段结肠均有延长，结合转动指数研究，发现直肠乙状结肠部位的延长更显著。两种疾病的肛门直肠括约肌静息压、收缩压和松弛压均无明显异常，但两者的顺应性和排便阈值均明显增高，其中功能性便秘的感觉阈值有增加。结论 IBS便秘型结肠运动紊乱主要在右半结肠，功能性便秘的结肠动力改变主要在直肠乙状结肠部为多。说明两者的结肠运动方式改变是不同的，对两者的鉴别诊断有帮助。     

Altered bile acid metabolism in patients with constipation-predominant irritable bowel syndrome and functional constipation

Objective. Bile acids are derived from cholesterol and are potent physiological laxatives. The aim of this study was to investigate whether bile acid synthesis is altered in constipation. Material and methods. Female patients with constipation (23 IBS-C, 4 functional constipation (FC)) were studied and compared with non-constipated subjects (16 IBS-D, 20 healthy women). Body mass index (BMI), blood lipids, lanosterol, sitosterol, colonic transit (oro-anal transit time (OATT), reference=4.3 days) and stool frequency were measured. C4 (7-α-hydroxy-4-cholesten-3-one) levels reflecting bile acid synthesis were measured at 0800 h and 1300 h. Results. When all the groups of constipated and non-constipated subjects were compared, it was found that only stool frequency and OATT differed between groups (p <0.001). When constipated patients were categorized according to OATT, absence of the usual C4 increase at lunchtime was noted in 82% of patients with delayed OATT compared with 17% in subjects with normal OATT (p <0.001). Symptom severity did not differ between groups. A subset of the patients with severely delayed OATT had markedly elevated C4 levels. Conclusions. Patients with IBS-C and FC have marked changes in bile acid synthesis in relation to colonic transit. The diurnal rhythm is altered in the slow transit colon when there is no C4 peak at lunchtime. Alterations in bile acid metabolism may be implicated in the pathophysiology of constipation.     

Tegaserod: long-term treatment for irritable bowel syndrome patients with constipation in primary care

BACKGROUND: Tegaserod, a prokinetic 5-HT4 receptor agonist, has demonstrated efficacy and tolerability in irritable bowel syndrome (IBS) patients with constipation (IBS-C) in controlled clinical trials. Its use in primary care has not been investigated. AIM: To determine whether tegaserod is effective and well tolerated by primary care IBS-C patients. METHODS: Patients received tegaserod 6 mg b.i.d. for 12 weeks and were assessed for response, abdominal pain/discomfort, bloating, stool consistency/frequency and straining at weeks 4 and 12. Previous successful treatment with the withdrawn drug, cisapride, was noted. A 9-month study extension was offered to patients completing 12 weeks of tegaserod treatment. RESULTS: 212 patients entered the 12-week treatment period; 166 completed as planned. Response rates were 64.2% at week 4 and 70.3% at week 12. After 12 weeks, abdominal pain/discomfort and bloating were reduced from baseline (p < 0.0001; mean change -1.02 and -0.91 points, respectively), stool frequency increased (0.78-0.97 stools/day) and stool consistency improved (2.45-3.42; lumpy stools became softer). Tegaserod was well tolerated; the most common adverse events were headache (13.2%) and diarrhea (9.4%). One hundred and twenty patients entered the 9-month extension study, 85 completed and tegaserod continued to be well tolerated. CONCLUSIONS: In ambulatory primary care IBS-C patients, tegaserod is an effective and well-tolerated long-term treatment.     

便秘型肠易激综合征肛门直肠动力学的临床研究

目的　观察便秘型肠易激综合征 (IBS)的肛门直肠动力学改变。方法　采用灌注式测压装置测定 18例便秘型IBS患者和 15例健康人的肛门直肠压力、直肠对容量刺激的最低敏感量、最大耐受量及直肠顺应性。结果　便秘型IBS的直肠、肛门内外括约肌静息压力、内括约肌主动收缩压、模拟排便时直肠收缩压、内外括约肌净减压与对照组相比无显著性差异。肛门 直肠屏障压便秘型IBS组高于对照组 (P <0 0 5 )。直肠对容量刺激的最低敏感量便秘型IBS组低于对照组 (P <0 0 5 ) ,最大耐受量及顺应性均高于对照组 (P <0 0 1)。结论　便秘型IBS存在肛门直肠动力学异常 ,这种异常可能是导致便秘的原因     

便秘型肠易激综合征患者肛门直肠运动感觉功能及自主神经活性的变化

目的 研究便秘型肠易激综合征(C-IBS)患者肛门直肠感觉运动功能及自主神经活性变化,以探讨C-IBS的发病机制.方法 用电子气压泵及液流灌注压力监测系统对28例C-IBS患者和15名对照组进行肛门直肠测压检查.对其中12例C-IBS患者和8例健康志愿者,通过HRV频域分析比较两组交感神经张力的变化.结果 C-IBS患者的肛门内括约肌最大收缩压、最小抑制容量、直肠顺应性、初始感觉阈值、初次排便阈值、排便窘迫阈值、最大容量感觉阈值均明显低于对照组(P＜0.05).在C-IBS患者组及对照组中,P1/(P1 P2)在产生便意、排便窘迫、最大耐受时均显著高于基础静息状态(P＜0.05);C-IBS患者组P1/(P1 P2)在基础静息、产生初始感觉、产生便意、排便窘迫时显著高于对照组(P＜0.05).结论 C-IBS患者存在直肠感觉过敏和自主神经功能异常,直肠顺应性也显著低于对照组,可能是C-IBS的发病机制之一.     

便秘型和腹泻型肠易激综合征患者肛门直肠运动及直肠感觉功能的检测分析

目的研究便秘型和腹泻型肠易激综合征(IBS)患者肛门直肠运动及直肠感觉改变。方法对2000-01~2004-01广州医学院第二附属医院根据罗马Ⅱ标准入选的便秘型IBS30例,腹泻型IBS20例,正常对照组26例,进行肛门直肠运动功能及直肠感觉测定。结果(1)便秘型和腹泻型IBS肛门括约肌压力、肛门括约肌最大缩窄压和正常对照组相比差异无显著性(P>0.05);增加腹压时,肛门括约肌净增压腹泻型低于正常对照组(P<0.05);模拟大便时直肠和肛门括约肌出现同步收缩发生率便秘型IBS高于正常对照组(P<0.01)。(2)便秘型IBS直肠对容量刺激的最低敏感量、最大耐受性、顺应性明显高于正常对照组(P<0.01)。(3)腹泻型IBS直肠对容量刺激的最低敏感量、最大耐受性、顺应性明显低于正常对照组(P<0.01)。结论(1)IBS存在肛门直肠运动异常。(2)便秘型IBS直肠对容量刺激低敏感、高耐受、高顺应性,可能是引起便秘原因之一。(3)腹泻型IBS直肠对容量刺激存在高敏感、低耐受、低顺应性和肛门自控能力减弱,可能与腹泻有关。     

功能性便秘和便秘型肠易激综合征相关生活因素上的差异

目的比较功能性便秘（FC）与便秘型 IBS 患者相关生活因素的差异。方法纳入2011年2月至2014年12月的255例慢性便秘患者,其中 FC 170例,便秘型 IBS 85例。另纳入同期1年内无消化道症状的170名健康者作为对照组。收集所有纳入者的人口学基本资料、生活习惯资料等。先行单因素分析,将差异有统计学意义的变量纳入多因素 Logistic 回归分析。再将 FC 和便秘型 IBS 的各因素纳入决策树模型,分析不同分类下影响因素的作用。结果单因素分析显示,FC 组与便秘型 IBS 组各生活因素比较差异均无统计学意义（P 均＞0．05）。多因素 Logistic 回归分析显示,与 FC 组比较,便秘型 IBS 组未发现独立保护或危险因素。经过决策树模型分析,最终纳入 BMI、每日饮水量和便秘家族史3个变量,当 BMI＜23．56 kg／m2（除外18．74～＜19．83 kg／m2）时,患 FC 的概率高（最高达79．75％）;当BMI 为18．74～＜19．83 kg／m2,每日饮水量少（＜1 L）时,患 FC 的概率高（66．67％）;当 BMI≥23．56 kg／m2,有便秘家族史时,患便秘型 IBS 的概率最高（70．00％）。该模型的整体预测准确率为64．6％（42／65）, AUC 值为0．688。结论FC 和便秘型 IBS 的发生与多种生活因素密切相关,BMI 低和每日饮水量少是FC 的影响因素,BMI 较高和有便秘家族史是便秘型 IBS 的影响因素。     

Differentiating functional constipation from constipation-predominant irritable bowel syndrome: management implications

Symptoms of constipation are commonly seen in medical practice. Once other medical causes have been excluded, distinguishing patients who have constipation-predominant irritable bowel syndrome (IBS) from those with functional constipation has been considered useful in terms of planning management. However, the criteria used to distinguish IBS from functional constipation are arguably arbitrary, and the availability of new therapeutic approaches may render such distinctions of little practical relevance. In this article, the author presents a review of the management implications of differentiating constipation-predominant IBS from functional constipation.     

Tegaserod is safe, well tolerated and effective in the treatment of patients with non-diarrhoea irritable bowel syndrome

OBJECTIVE: To evaluate the safety/tolerability and efficacy of tegaserod, a 5-HT4 receptor partial agonist, in the treatment of patients with non-diarrhoea irritable bowel syndrome (non-D-IBS) in Switzerland. METHODS: This was an 8-week, open-label, prospective, multicentre study. Patients (> or =18 years old) met the Rome II diagnostic criteria for IBS, excluding those with diarrhoea for > or =14 days in the previous 3 months. Details of IBS symptoms experienced in the preceding week were recorded at visit 1 (day 1). Eligible patients received 6 mg tegaserod twice daily for 8 weeks. Adverse events (AEs) and serious AEs were recorded, along with detailed assessment of diarrhoeal episodes. Efficacy assessments included the overall number and percentage of responders after 8 weeks' treatment. RESULTS: A total of 850 patients (72% women; mean age, 51.4 years) were enrolled, and 843 received at least one dose of tegaserod. AEs were reported in 38% of patients, of which 13% were drug-related. Diarrhoea occurred early during treatment (13% in the first week, 7% thereafter), was mild to moderate in severity, was transient and was resolved with continued treatment. In total, 208 patients left the study early, primarily due to AEs. Diarrhoea accounted for 68 of these discontinuations. Nine serious AEs were reported but these were not related to tegaserod treatment. Sixty-six percent of patients responded to tegaserod on the Subject's Global Assessment of relief after 8 weeks. Benefits were also seen across individual IBS symptoms. CONCLUSION: Tegaserod (6 mg twice daily) appears to be safe, well-tolerated and effective in the treatment of non-D-IBS over 8 weeks.