便秘型肠易激综合征的SERT基因多态性及其与患者临床疗效的关系

目的探讨便秘型肠易激综合征(C-IBS)5-羟色胺转运蛋白(SERT)基因多态性及其与替加色罗临床疗效的关系。方法利用PCR检测84例符合罗马Ⅲ诊断标准的C-IBS患者和103例健康对照者外周血的SERT启动子区域(5-HTTLPR)与第2内含子可变数目串联重复序列(VNTRs)两个基因多态性,对其中入选65例的C-IBS患者给予4周替加色罗6 mg、2次/d,评估治疗前后患者临床症状及便秘程度。结果 C-IBS患者L/L基因型频率比对照组明显升高(25.0%vs 7.8%,P<0.05)。治疗后C-IBS患者各基因型组替加色罗治疗的有效率有统计学差异差异,表现为总体疗效和单个症状改善S/S基因型和S/L基因型均优于L/L基因型(S/S 93.1%、S/L 70.6%、L/L 33.3%,P<0.01)。结论 SERT基因多态性可能与C-IBS相关;SERT基因多态性影响替加色罗对C-IBS患者的疗效。     

基因多态性与肠易激综合征的关系及其对药效的影响

目的探讨5-羟色胺转运体（SERT）基因启动子区域（5-HTTLPR）与第2内含子可变数目串联重复序列（VNTRs）多态性在正常人及肠易激综合征（IBS）患者的分布及对替加色罗治疗便秘型IBS（C-IBS）疗效的影响。方法用PCR检测87例IBS和96例对照者外周血2个基因的多态性;给予41例C-IBS患者4周替加色罗6mg,2次／d,治疗前后评估临床症状及便秘程度。结果IBS组5-HTTLPR基因型频率是S／S：52．9％,S／L：31．0％,L／L：16．1％;对照组分别为57．3％,35．4％及7．3％;IBS组VNTRs基因型频率是STin2．10／10：2．3％,STin2．12／10：17．2％,STin2．12／12：80．5％;对照组分别为2．1％,11．4％及86．5％;两组差异无统计学意义（P〉0．05）,但C-IBS组的I／L频率比对照组显著高（25.0％比7.3％,P〈0．05）。治疗后症状缓解率S／S型为85.0％,S／L型为70．0％,均显著优于L／L型的36．4％（P〈0．05）;主体症状评分和单个症状（排便次数、粪便性状、便后排空感等）改善在S／S和L／S型均优于L／L型（P〈0．05）。结论SERT基因多态性总体与IBS发病无关,但L／L型更易患C-IBS。替加色罗对C—IBS的疗效受基因型影响,L／L型疗效较差。     

5-羟色胺转运体基因多态性与肠易激综合征的相关性

目的:探讨SERT基因启动子区5-HTTLPR和内含子2 VNTRs多态性在肠易激综合征(IBS) 中的意义．方法:采用PCR方法对51例腹泻型IBS(D- IBS)、58例便秘型IBS(C-IBS)、38例便秘腹泻交替型IBS(A-IBS)患者与48例健康对照者SERT基因启动子区5-HTTLPR和内含子2 VNTRs多态性进行比较分析．结果:C-IBS组L／L基因型及L等位基因频率显著高于对照组(31．0％vs 8．3％,X2=8．229, P<0．05;47．4％vs29．2％,X2=7．342,P<0．05), D-IBS组S／S基因型频率和S等位基因频率显著高于A-IBS和C-IBS组(S／S:56．9％vs 36．8％, 36．2％,P<0．05;S:71．6％vs 56．6％,52．6％, P<0．05),L／L基因频率显著低于A-IBS和C-IBS 组(9．8％vs 28．1％,P<0．05)．IBS各组与对照组之间内含子2 VNTRs多态性分布无显著性差异(P>0．05)．结论:具有L／L基因型和L等位基因的人更易患C-IBS,具有S／S基因型和S等位基因的人更易患D-IBS,L／L基因型可能是D-IBS的保护因素之一．     

The Serotonin Transporter Polymorphism rs25531 Is Associated with Irritable Bowel Syndrome

Irritable bowel syndrome is a frequent gastrointestinal disorder of unknown etiology. The serotonin transporter regulates the intensity and duration of serotonin signaling in the gut and is, therefore, an attractive candidate gene for irritable bowel syndrome. Previous studies investigating the 5-HTTLPR and Stin2 VNTR polymorphisms of the serotonin transporter have proved inconclusive. In this exploratory study we therefore expanded the search for a possible association of the serotonin transporter with irritable bowel syndrome to include not only the 5-HTTLPR and Stin2 VNTR length polymorphisms, but also the functional single nucleotide polymorphism rs25531. We genotyped 186 patients with irritable bowel syndrome and 50 healthy control subjects raging in age from 18 to 70 years. Carriers of the rare G allele of rs25531 had approximately threefold increased odds of irritable bowel syndrome compared with healthy controls (OR 3.3, 95% CI 1.1–9.6). Our findings suggest that further investigation of the possible role of the serotonin transporter in the etiology of IBS is warranted.     

Serotonin transporter gene polymorphism in irritable bowel syndrome

OBJECTIVES: Serotonin is a key mediator of intestinal peristalsis, and after it is secreted, it is effectively cleansed from the neuronal gap by means of a high affinity substance called serotonin transporter (SERT), which depends on the Na+ and Cl- ions localized in the presynaptic neuronal membranes. The aim of this study was to investigate SERT polymorphism in patients with irritable bowel syndrome (IBS). METHODS: SERT gene polymorphism was assessed by polymerase chain reaction on DNA chains obtained from leukocytes in serum samples from 54 patients diagnosed with IBS and 91 healthy subjects. The polymorphism of two regions (variable number tandem repeats and the SERT gene-linked polymorphic region [5-HTTLPR]) of SERT was assessed. RESULTS: SERT polymorphisms were found to be similar in healthy subjects and IBS patients (p > 0.05). IBS patients were divided into three groups: diarrhea predominant (n = 18), constipation predominant (n = 26), and alternating diarrhea and constipation (n = 10). These groups were compared with respect to gene polymorphism, and it was found that the 5-HTTLPR allele S/S genotype occurred with greater frequency in the constipation predominant group than in the other two subgroups (p < 0.05), and L/S genotype frequency in the diarrhea predominant group was higher than those in the constipation and control groups. CONCLUSIONS: No relationship was found between IBS and SERT gene polymorphism. It is conceivable that the presence of the S/S genotype in IBS patients carries an increased risk of the constipation predominant type of IBS, whereas the presence of the 5-HTTLPR allele L/S genotype carries an increased risk of the diarrhea predominant type.     

肝郁脾虚型肠易激综合征与5-羟色胺转运体基因多态性的关系

[目的]探讨肝郁脾虚型肠易激综合征（IBS）与5-羟色胺转运体（SERT）基因多态性的关系。[方法]用多聚酶链式反应技术（PCR）对50例肝郁脾虚型IBS患者与96例健康对照者SERT基因的启动子区（5-HTTLPER）和内含子2可变数目串联重复序列（VNTRs）多态性进行研究。[结果]肝郁脾虚型组5-HTTLPR基因频率分布是S／S 40．0％，L／S54．0％，L／L11．1％。健康对照组的分布频率是S／S57．3％，L／S35．4％，L／L7．3％。2组之间比较差异无统计学意义（P〉0．05），但肝郁脾虚型组的L／S基因频率比对照组明显升高（P〈0．05）。2组VNTRs区的多态性比较差异无统计学意义（P〉0．05）。[结论]拥有L／S基因型可能是肝郁脾虚型IBS的多个易患因素之一。     

Association of distinct alpha(2) adrenoceptor and serotonin transporter polymorphisms with constipation and somatic symptoms in functional gastrointestinal disorders

BACKGROUND: The role of genetics in the phenotypic manifestations of irritable bowel syndrome (IBS) is unclear. Our aims were: (1) to compare the prevalence of polymorphisms of alpha 2 (alpha(2)) adrenoceptors, norepinephrine transporter, and serotonin transporter protein (soluble carrier protein member 4 (SLC6A4)) promoter in patients with lower functional gastrointestinal disorders (FGID) and in healthy controls; and (2) to test associations of these genetic variations with symptoms of IBS and high somatic symptom scores. METHODS: Validated bowel and somatic symptom questionnaires characterised the phenotype: 90 with IBS constipation (IBS-C), 128 IBS diarrhoea, 38 IBS alternating bowel function, and 20 chronic abdominal pain. Logistic regression analyses assessed associations of different polymorphisms for alpha(2) adrenoceptor and SLC6A4 with IBS or chronic abdominal pain phenotypes and high somatic score. RESULTS: Two distinct polymorphisms independently appeared to be associated with the phenotype IBS-C: alpha(2C) Del 322-325 (odds ratio (OR) 2.48 (95% confidence interval (CI) 0.98, 6.28); p = 0.05) and alpha(2A) -1291 (C-->G) (OR 1.66 (95% CI 0.94, 2.92); p = 0.08) relative to wild-type. Overall, the alpha(2C) Del 322-325 polymorphism (alone or combined with other polymorphisms) was also significantly associated with a high somatic symptom score (OR 2.2 (95% CI 1.06, 4.64); p = 0.03). Combinations of polymorphisms were also associated with high somatic scores. CONCLUSION: Functionally distinct alpha(2A) and alpha(2C) adrenoceptor and serotonin transporter polymorphisms are associated with constipation and high somatic symptoms in patients with lower functional gastrointestinal disorders, although the strength of the genetic contribution to the phenotype is unclear.     

Safety and tolerability of tegaserod in patients with irritable bowel syndrome and diarrhea symptoms

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 > or =2 Rome diarrhea criteria > or =25% 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.     

Tegaserod: a new 5-HT4 agonist.

Tegaserod is a medication that has been shown to be of benefit in women with irritable bowel syndrome (IBS) associated with abdominal pain, bloating, and constipation. Tegaserod is a selective serotonin receptor subtype 4 partial agonist designed to interact with the network of cells and nerves throughout the gastrointestinal tract that use serotonin. Tegaserod has been shown to modulate both gastrointestinal motility and visceral sensitivity. Specifically, it increases the peristaltic reflex and decreases visceral sensitivity. Clinical studies have shown that tegaserod improves symptoms of abdominal pain, bloating, and constipation in women with IBS. This article discusses the role of serotonin in gastrointestinal tract physiology, the structure and pharmacokinetic profile of tegaserod, and clinical applications of this new drug.     

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.     

肠易激综合征患者5-羟色胺转运体的基因多态性

目的 探讨5-羟色胺转运体(SERT)基因多态性在肠易激综合征(IBS)中的意义。方法 用PCR方法对48例健康对照和30例便秘型IBS(C-IBS)、32例腹泻型IBS(D-IBS)和19例交替型IBS(A-IBS)患者SERT基因的VNTRs和5-HTTLPR区多态性进行研究。结果 VNTRs区：IBS患者STin2．12／10基因型频率明显高于对照组,各亚型间基因型频率差异无显著性。5-HTTLPR区：C-IBS组L／L频率显著高于D-IBS、A-IBS和对照组;D-IBS、A-IBS组IMS频率显著高于C-IBS组。C-IBS组12／12-L／L基因型联合的频率显著高于A-IBS和D-IBS组。结论 SERT基因VNTRs区STin2．12／10基因型可能与IBS相关,具有L／L基因型以及12／12-L／L基因型联合的人群可能更易患C-IBS,IMS基因型的人群易患D-IBS和A-IBS。     

Constipation: evaluation and treatment of colonic and anorectal motility disorders

This article focuses on the colonic and anorectal motility disturbances that are associated with chronic constipation and their management. Functional chronic constipation consists of three overlapping subtypes: slow transit constipation, dyssynergic defecation, and irritable bowel syndrome with constipation. The Rome criteria may serve as a useful guide for making a clinical diagnosis of functional constipation. Today, an evidence-based approach can be used to treat patients with chronic constipation. The availability of specific drugs for the treatment of chronic constipation, such as tegaserod and lubiprostone, has enhanced the therapeutic armamentarium for managing these patients. Randomized controlled trials have also established the efficacy of biofeedback therapy in the treatment of dyssynergic defecation.     

Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial.

BACKGROUND AND AIMS: Chronic constipation is a common gastrointestinal disorder. The aim of this study was to evaluate the efficacy, safety, and tolerability of tegaserod, a serotonin subtype 4 receptor partial agonist in patients with chronic constipation. METHODS: This was a randomized, double-blind, placebo-controlled study. After a 2-week baseline, patients received tegaserod 2 mg twice daily (n = 450), tegaserod 6 mg twice daily (n = 451), or placebo (n = 447) for 12 weeks, followed by a 4-week withdrawal period. Responders were those patients having been treated for at least 7 days with an increase of > or =1 complete spontaneous bowel movement/week vs. baseline during weeks 1-4 (primary variable) and weeks 1-12 (secondary variable). Other secondary variables included patient assessment of constipation symptoms (number of bowel movements, stool form, abdominal bloating/distention, straining, and abdominal pain/discomfort), and global assessment of constipation and bowel habits. RESULTS: Responder rates for complete spontaneous bowel movement during weeks 1-4 were significantly greater ( P < 0.0001) in the tegaserod 2 mg twice daily (41.4%) and 6 mg twice daily groups (43.2%) vs. placebo (25.1%). This effect was maintained over 12 weeks. Statistically significant improvements over placebo were observed across the majority of secondary variables for both tegaserod doses. No rebound effect was observed after treatment withdrawal. Tegaserod was well tolerated; headache and nasopharyngitis, the most frequent adverse events, were more common in the placebo group than in either tegaserod group. CONCLUSIONS: Over 12 weeks, tegaserod treatment produced significant improvements in chronic constipation symptoms and was also safe and well tolerated.     

A randomized, multicenter comparison of polyethylene glycol laxative and tegaserod in treatment of patients with chronic constipation

OBJECTIVE: Polyethylene glycol (PEG) 3350 (MiraLax) and tegaserod (Zelnorm), a serotonin subtype 4 receptor partial agonist, are currently approved for treatment of constipation. This study was designed to compare the efficacy of each product over a 4-wk treatment period. METHODS: Study patients who met defined criteria for chronic constipation were randomized in this open-labeled, parallel, multicenter study to receive the PEG laxative as a single daily dose of 17 g or tegaserod tablets 6 mg b.i.d., for 28 days. As a primary end point, treatment success was defined for each patient as relief of modified ROME criteria for constipation for 50% or more of their treatment weeks. Various secondary measures were also assessed. An interactive voice response system (IVRS) recorded patient reported daily bowel movement experience and study efficacy and safety information. RESULTS: A total of 237 patients were enrolled and received treatment at one of 25 centers. Successful treatment according to the primary end point was seen in 50.0% of the PEG and 30.8% of tegaserod patients (P= 0.003). By treatment weeks 3 and 4, significantly more PEG patients were successfully treated according to primary and secondary response definitions. PEG patients experienced more bowel movements per week (P= 0.019) and had significantly greater improvement in constipation symptoms (P= 0.016) based on results from a validated patient self-reported questionnaire. Tegaserod patients experienced a significantly higher incidence of headaches. Otherwise, there were no significant differences in adverse events. CONCLUSIONS: While PEG laxative and tegaserod are safe for their intended use in chronic constipation, PEG had superior efficacy, caused fewer headaches, and produced greater improvement of constipation symptoms.     

Anorectal manometry in irritable bowel syndrome: differences between diarrhoea and constipation predominant subjects.

Anorectal manometry with balloon distension was performed on 28 patients with diarrhoea predominant irritable bowel syndrome, 27 patients with constipation predominant irritable bowel syndrome and 30 normal controls. In the diarrhoea predominant group balloon volumes required to perceive the sensations of gas, stool, urgency of defecation and discomfort were significantly lower than in controls or constipation predominant patients (p less than 0.001). Diarrhoea predominant patients also had a significantly lower rectal compliance than controls or constipation predominant patients (p less than 0.03) but showed no difference in motor activity induced by distension. When the constipation predominant patients were compared with controls the only significant difference that emerged was in the volume at which discomfort was perceived. No significant differences between constipated subjects and controls were found in the distension induced motor activity. Symptom severity and psychological parameters were also recorded and the diarrhoea predominant patients were found to be more anxious than those with constipation (p = 0.04). It proved possible (by comparison with the control group) to identify three abnormal rectal subtypes in patients with irritable bowel syndrome. These were a sensitive rectum (low sensation thresholds, normal or low rectal pressure), a stiff rectum (normal or low sensation thresholds, high pressure) and an insensitive rectum (high sensation thresholds, normal or high pressure) and their distribution varied considerably depending on bowel habit. Some form of rectal abnormality was identified in 75% of diarrhoea predominant patients compared with 30% of constipation predominant subjects (p = 0.002). A sensitive rectum was a particular feature of diarrhoea predominant patients being observed in 57% of patients compared with only 7% of the constipated group (p less than 0.001).     

A randomised controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation

BACKGROUND: It has been proposed that treatments for irritable bowel syndrome with constipation (IBS-C) should provide rapid symptomatic relief, be intermittent, and effective upon repeated use. AIMS: To evaluate the efficacy and safety of tegaserod on IBS symptoms, and its impact on quality of life and health economic measures. PATIENTS: Women (> or = 18 years of age) with IBS-C according to the Rome II criteria. METHODS: Prospective, double blind, placebo controlled, randomised trial. Women with IBS-C either received tegaserod 6 mg twice daily or placebo for one month. Patients with at least a partial response entered a treatment free interval. Upon symptom recurrence, tegaserod treated patients were re-randomised to tegaserod or placebo for an additional month. Primary efficacy variables were response (overall IBS symptoms and abdominal discomfort/pain) to first and repeated treatment. Analysis was by intention to treat. RESULTS: 2660 patients and 1191 patients were randomised for first and repeated treatment respectively. Tegaserod was superior to placebo for each primary efficacy variable (first treatment: 33.7% v 24.2% responders respectively for relief of IBS symptoms and 31.3% v 22.1% for relief of abdominal discomfort/pain; repeated treatment: 44.9% v 28.7%, and 42.4% v 27.1%, all p < 0.0001). Tegaserod was superior to placebo for every secondary efficacy variable (relief of abdominal discomfort/pain, bloating and constipation; stool frequency and consistency). A response to tegaserod was observed within the first treatment week. Tegaserod produced greater satisfaction, work productivity, and improved quality of life than placebo (p < 0.05). CONCLUSION: Tegaserod provides rapid and sustained relief of IBS-C symptoms both during first and repeated treatment.     

Relation among personality and symptoms in nonulcer dyspepsia and the irritable bowel syndrome

The importance of personality traits in nonulcer dyspepsia and irritable bowel syndrome is a controversial issue. We wished to assess the distribution of abnormal personality traits in nonulcer dyspepsia and the irritable bowel syndrome, define any relation among personality and symptoms, and determine whether personality factors discriminate among patients with functional, psychiatric, or organic gastrointestinal diseases. Patients with nonulcer dyspepsia (n = 31), irritable bowel syndrome (n = 67), organic gastrointestinal disease (n = 64), somatoform disorder (n = 36) and healthy controls (n = 128) were studied. Before diagnostic evaluation by an independent physician, all patients completed the Minnesota Multiphasic Personality Inventory and a symptom questionnaire. Symptom scores for abdominal pain and the Manning criteria, which is considered to be diagnostic for the irritable bowel syndrome, were evaluated. Personality scales in patients with nonulcer dyspepsia, irritable bowel syndrome, and organic disease were very similar. However, patients in the other groups differed from somatoform disorder on nearly all scales. In nonulcer dyspepsia, irritable bowel syndrome, and organic disease, hypochondriasis weakly correlated with pain. Subgroups of irritable bowel syndrome patients with predominant constipation and those with predominant diarrhea had similar personality traits, although hypomania was minimally increased in constipation. Patients who fulfilled the Manning criteria for irritable bowel syndrome had more psychological distress than those who did not. The Minnesota Multiphasic Personality Inventory correctly classified somatoform disorder and health 81% and 75% of the time, respectively, but it classified nonulcer dyspepsia and irritable bowel syndrome correctly in only 32% and 34% of cases. Our results suggest that psychopathology may not be the major explanation for functional gastrointestinal disorders.     

Bladder smooth muscle dysfunction in patients with irritable bowel syndrome.

Urodynamic studies were carried out on 30 patients with irritable bowel syndrome and 30 matched controls. Fifty per cent of the irritable bowel patients compared with only 13% of the control group had evidence of bladder dysfunction (p = 0.006). In the irritable bowel group detrusor instability was observed in 10 patients compared with only one control subject (p = 0.008). A steep cystometrogram occurred in five irritable bowel patients and three controls (NS). Detrusor instability was most common in patients with a bowel habit characterised by alternating constipation and diarrhoea. This is the first study to provide objective evidence that patients with irritable bowel syndrome may have a disorder of smooth muscle or its innervation that is not confined to the gastrointestinal system.