Effects of cimetropium bromide on gastrointestinal transit time in patients with irritable bowel syndrome

Cimetropium bromide is a new antimuscarinic compound with strong antispasmodic activity. The aim of this study was to evaluate the effects of oral cimetropium bromide on total gut transit time in patients with irritable bowel syndrome. Forty patients, divided according to their initial total gastrointestinal transit times and presenting symptoms, were treated with cimetropium bromide 50 mg t.d.s. or placebo for 1 month according to a double-blind, parallel group design. Before and after treatment all subjects ingested 24 radio-opaque markers. The total intestinal transit time was determined by evaluating the rate of disappearance of markers from plain X-ray films of the abdomen taken every 24 h for 4 days. Pain and bowel habits were also monitored. Seven patients did not complete the study. Cimetropium bromide significantly (P less than 0.01) shortened the whole gut transit time in patients with prolonged transit time (80.8 +/- 4.0 h before vs 60.8 +/- 6.7 h after treatment) and improved the global clinical condition significantly compared with placebo (P = 0.029). In patients with a short total intestinal transit time, cimetropium bromide had no effect on whole gut transit time and did not significantly improve symptoms. The results of this study indicate that oral cimetropium bromide is effective both objectively and subjectively in a subgroup of irritable bowel syndrome patients with constipation.     

Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome

Background:

Visceral hypersensitivity plays a major role in the pathophysiology of irritable bowel syndrome, as shown by balloon distension studies. 5-HT3 receptors on afferent nerves may modulate visceral sensitivity and be the target of new treatments for irritable bowel syndrome.

Aim:

To evaluate the effects of alosetron, a potent and selective 5-HT3 antagonist, on the perception of colonic distension by patients with irritable bowel syndrome, and on the colonic compliance to distension with a barostat.

Methods:

Twenty-five irritable bowel syndrome patients were included in a randomized double-blind parallel group trial; data were available for 22 (Rome criteria; 48 ± 11 years; 13 men and nine women). Patients were treated for 7 days with placebo (n = 6), alosetron 0.25 mg b.d. (n = 8) or alosetron 4 mg b.d. (n = 8). On day 6, a barostat bag was placed in the left colon. On day 7, after an overnight fast, isobaric phasic distensions were performed (4 mmHg steps, 5 min) up to the step triggering a sensation of abdominal pain.

Results:

Groups were comparable at inclusion (age, sex, symptoms, bowel habits). There were no differences between treatment groups in pressure recorded within the bag at the time of first sensation of abdominal pain. However, bag volumes were significantly increased. At the first sensation threshold, median volume differences of 61 mL and 90 mL (P = 0.028) were recorded with alosetron 0.25 mg b.d. and 4 mg b.d., respectively. At the threshold of abdominal pain, these differences were 71 mL (P = 0.039) and 84 mL (P = 0.017). Colonic compliance increased from 5.9 mL/mmHg on placebo to 7.6 mL/mmHg on alosetron 0.25 mg b.d. and to 9.8 mL/mmHg (P = 0.034) on alosetron 4 mg b.d.

Conclusion:

Alosetron increases the compliance of the colon to distension, and could thereby contribute to changes in perception of colonic distension and improvement in the symptoms of irritable bowel syndrome.

     

Effect of alosetron on left colonic motility in non-constipated patients with irritable bowel syndrome and healthy volunteers

BACKGROUND: Alosetron is a 5-hydroxytryptamine-3 receptor antagonist reducing symptoms in female patients with diarrhoea-predominant irritable bowel syndrome, and is known to increase the colonic transit time. AIM: To study the effect of alosetron on left colonic phasic motility in ambulant non-constipated patients with irritable bowel syndrome and healthy volunteers. METHODS: In a double-blind, randomized, crossover design, 10 patients with irritable bowel syndrome and 12 sex- and age-matched volunteers were treated for two 7-day periods with alosetron, 4 mg b.d., or placebo b.d. On day 6 of each treatment period, a six-channel solid-state manometric catheter was positioned in the left colon and 24 h motility was studied on day 7. The periprandial phasic motility around dinnertime was evaluated in the descending and sigmoid colon. The high-amplitude propagated contraction frequency and characteristics were calculated. RESULTS: Alosetron appeared to increase the overall periprandial frequency in the sigmoid colon (P=0.043) and the mean amplitude of colonic contractions in the descending colon (P=0.007). The high-amplitude propagated contraction frequency was higher on alosetron during the second half of the day for patients with irritable bowel syndrome (P=0.002), with increased mean propagation length of high-amplitude propagated contractions (P=0.001). The stool frequency (P=0.024) and stool consistency score (P=0.002) were decreased by alosetron. CONCLUSIONS: The 5-hydroxytryptamine-3 receptor antagonist alosetron marginally increased left colonic periprandial phasic motility. Alosetron increased the number and propagation length of high-amplitude propagated contractions, which were paradoxically accompanied by a decrease in stool frequency and a firming of stool consistency.     

Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome

BACKGROUND: Gabapentin has been shown to reduce elements of central sensitization in human experimental hyperalgesia. It remains uninvestigated whether gabapentin has beneficial effects for irritable bowel syndrome associated with visceral hypersensitivity. AIMS: To evaluate the effects of gabapentin on sensory and motor function of the rectum in patients with diarrhoea-predominant irritable bowel syndrome. METHODS: Forty patients with diarrhoea-predominant irritable bowel syndrome completed this randomized, double-blind, placebo-controlled, parallel-grouped study. All patients received a barostat study and were subsequently randomized for 5-day treatment with gabapentin 300 mg/day and then 600 mg/day or placebo. On day 6, after subjects had their morning dose, the barostat experiment was repeated. RESULTS: The threshold pressures for bloating, discomfort and pain significantly increased after gabapentin, but not after placebo. Significant increase in the pressure and corresponding wall tension inducing discomfort or pain were observed in the gabapentin group, but not in the placebo group. Rectal compliance significantly increased after gabapentin, but not after placebo. The postprandial increase of rectal tone was not affected by gabapentin. CONCLUSION: Our results show that gabapentin reduces rectal sensory thresholds through attenuating rectal sensitivity to distension and enhancing rectal compliance in diarrhoea-predominant irritable bowel syndrome patients. The clinical efficacy of this drug in irritable bowel syndrome patients warrants investigation.     

Gut-focused hypnotherapy normalizes disordered rectal sensitivity in patients with irritable bowel syndrome

BACKGROUND: We have previously shown that hypnotherapy alters rectal sensitivity in some patients with irritable bowel syndrome. However, this previous study used incremental volume distension of a latex balloon, which might be susceptible to subject response bias and might compromise the assessment of compliance. In addition, the study group was symptomatically rather than physiologically defined. AIM: To assess the effect of hypnotherapy on rectal sensitivity in hypersensitive, hyposensitive and normally sensitive irritable bowel syndrome patients using a distension technique (barostat) that addresses these technical issues. METHODS: Twenty-three irritable bowel syndrome (Rome I) patients (aged 24-72 years) were assessed before and after 12 weeks of hypnotherapy in terms of rectal sensitivity, symptomatology, anxiety and depression. Normal values for sensitivity were established in 17 healthy volunteers (aged 20-55 years). RESULTS: Compared with controls, 10 patients were hypersensitive, seven hyposensitive and six normally sensitive before treatment. Following hypnotherapy, the mean pain sensory threshold increased in the hypersensitive group (P = 0.04) and decreased in the hyposensitive group, although the latter failed to reach statistical significance (P = 0.19). Normal sensory perception was unchanged. Sensory improvement in the hypersensitive patients tended to correlate with a reduction in abdominal pain (r = 0.714, P = 0.07). CONCLUSION: Hypnotherapy improves abnormal sensory perception in irritable bowel syndrome, leaving normal sensation unchanged.     

Effect of octreotide on mouth-to-caecum transit time in healthy subjects and in the irritable bowel syndrome

The effect of a single subcutaneous injection of octreotide (50 micrograms) on mouth-to-caecum transit time was determined in patients with the irritable bowel syndrome who complained of bowel frequency, and in healthy volunteers. The assessment of mouth-to-caecum transit time was performed by monitoring breath hydrogen concentration and noting a sustained 10 p.p.m. rise after ingestion of lactulose 40 ml. Measurements were performed fasting, and on a separate day, after a standard breakfast which included 40 ml lactulose. The studies were performed double-blind in a pre-determined random order. Octreotide prolonged mouth-to-caecum transit time in irritable bowel syndrome patients and healthy subjects by factors of 2.4 and 2.6 after lactulose when fasting, respectively, and by factors of 2.8 and 2.6 after the breakfast which contained lactulose. The upper gastrointestinal transit rate was similar in irritable bowel syndrome patients and healthy controls.     

Single doses of ritodrine delay orocaecal transit in patients with irritable bowel syndrome.

The lactulose hydrogen breath test was used to assess the effect of a single dose of the beta 2-adrenoceptor agonist ritodrine on orocaecal transit time in 11 patients (three men) with irritable bowel syndrome. Transit time (median values, range) was significantly longer (P less than 0.01) after ritodrine than after placebo (120, 50-200 vs 75, 40-100 min). Median heart rate was similar before treatments whereas the maximal increase in heart rate was significantly greater (P less than 0.01) after ritodrine than after placebo.     

Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear. AIM: To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome. METHODS: Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves. RESULTS: Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18-30) and 30 (27-45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis. CONCLUSIONS: Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.     

肠易激综合征患者血浆胃肠激素含量的变化

目的探讨胃肠激素含量的变化与肠易激综合征(IBS)的关系. 方法采用放射免疫分析方法检测了43例IBS患者血浆中胃泌素、胃动素、胰高糖素的含量,并与20例正常人进行了对照.结果IBS患者血浆中胃泌素及胃动素含量高于对照组(P《0.01),腹泻型IBS患者血浆中胰高糖素含量低于对照组,便秘型IBS患者的胰高糖素含量则高于对照组(P《0.01). 结论胃肠激素异常与IBS的发病有相关性.     

Effect of long-term treatment with octreotide on rectal sensitivity in patients with non-constipated irritable bowel syndrome

BACKGROUND: Acute administration of octreotide reduces visceral perception and therefore has been suggested as potential treatment for irritable bowel syndrome. Whether prolonged treatment with octreotide also reduces visceral sensitivity and improves gastrointestinal symptoms remains, however, unknown. AIM: To investigate the effect of a slow release preparation of octreotide on rectal sensitivity and symptoms in irritable bowel syndrome patients. METHODS: Forty-six non-constipated irritable bowel syndrome patients (52% female, 19-63 years) participated. Before and after 8 weeks of treatment with octreotide (Sandostatin LAR 20 mg i.m.) or placebo, patients underwent a barostat study to assess the rectal sensitivity. During a 2-week run-in period and treatment, abdominal pain, defecation frequency, consistency and symptom relief were scored weekly. RESULTS: Octreotide, but not placebo, significantly increased the threshold for first sensation. Thresholds for urge to defecate and discomfort/pain and rectal compliance were not altered by either treatment. Octreotide improved stool consistency compared with placebo (loose stools after eight weeks: octreotide: 52%, placebo: 81%, P < 0.05). In contrast, abdominal pain and defecation frequency were not affected. CONCLUSIONS: Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve irritable bowel syndrome symptoms.     

肠易激综合征患者血浆胃肠激素含量的变化

目的 探讨胃肠激素含量的变化与肠易激综合征（IBS）的关系。方法 采用放射免疫分析方法检测了43例IBS患者血浆中胃泌素、胃动素、胰高糖素的含量,并与20例正常人进行了对照。结果IBS患者血浆中胃泌索及胃动素含量高于对照组（P<0.01）,腹泻型IBS患者血浆中胰高糖素含量低于对照组,便秘型IBS患者的胰高糖素含量则高于对照组（P<0.01）。结论 胃肠激素异常与IBS的发病有相关性。     

5-HT4 receptor antagonism in irritable bowel syndrome: effect of SB-207266-A on rectal sensitivity and small bowel transit

BACKGROUND: Pre-clinical studies indicate that the 5-hydroxytryptamine (5-HT)4 receptor may be involved in the pathophysiology of irritable bowel syndrome and that antagonism of this receptor may be an effective therapeutic strategy. AIM: To investigate the effects of SB-207266-A, a selective 5-HT4 receptor antagonist on rectal sensitivity and small bowel transit in patients with irritable bowel syndrome. METHODS: Eighteen patients with diarrhoea-predominant irritable bowel syndrome and a history of increased rectal sensitivity were randomized to receive either SB-207266-A (20 mg) or placebo for 10 days. Following a washout period, patients were then crossed over to receive the alternative therapy for 10 days. Rectal sensitivity and orocaecal transit time were assessed on day 10 of each treatment period. In addition, patients were asked whether they had experienced any changes in their symptoms. RESULTS: Fifteen patients completed the study. SB-207266-A significantly increased orocaecal transit time towards normal (placebo: 5.3 h (4.0-7.2 h), mean (IQR) vs. SB-207266-A: 6.5 h (4.8-8.0 h); P=0.027) and tended to decrease rectal sensitivity (volume to discomfort 89 mL (60-150 mL), geometric mean (IQR) vs. 107 mL (75-150 mL); P=0.134). Eleven out of 15 patients reported symptomatic improvements with SB-207266-A but none with placebo. SB-207266-A was well tolerated. CONCLUSION: Our results support a role for the 5-HT4 receptor in the pathophysiology of irritable bowel syndrome and suggest that the selective 5-HT4 antagonist, SB-207266-A, is worthy of further evaluation in this disorder.     

胃肠激素与肠易激综合征的相关性

目的：研究血管活性肠肽（VIP）,P物质（SP）和酷神经肽（NPY）在肠易激综合征（IBS）患者血浆和乙状结肠粘膜中的变化及临床意义。方法：用放射免疫法分别检测IBS患者（40例）和正常对照组（15例）血浆和乙状结肠粘膜中以上三种激素的含量。结果：IBS患者血浆和乙 状结肠粘膜中NPY含量明显低于对照组（P＜0．05）,而IP和SP在血浆中含量与正常对照组无显著差异（P＞0．015）,在乙状结肠粘膜中含量明显高于对照组（P＜0．01）,结论：P乙状结肠粘膜中三种胃肠激素的变化在IBS的腹痛,腹泻发病中有一定作用。     

Relationship between rectal sensitivity, symptoms intensity and quality of life in patients with irritable bowel syndrome

Background  Relationships between pain threshold during rectal distension and both symptoms intensity and alteration in quality of life (QoL) in irritable bowel syndrome (IBS) patients have been poorly evaluated.
Aim  To evaluate relationships between rectal sensitivity, IBS symptom intensity and QoL in a multicentre prospective study.
Methods  Rectal threshold for moderate pain was measured during rectal distension in IBS patients (Rome II), while IBS symptoms intensity was assessed by a validated questionnaire and QoL by the Functional Digestive Disorder Quality of Life questionnaire.
Results  Sixty-eight patients (44.2 ± 12.7 years, 48 women) were included. The mean rectal distending volume for moderate pain was 127 ± 35 mL while 45 patients (66%) had rectal hypersensitivity (pain threshold <140 mL). Rectal threshold was not significantly related either to overall IBS intensity score ( r  = −0.66, P  =   0.62) or to its different components, or to FDDQL score ( r  = 0.30, P  =   0.14). Among FDDQL domains, only anxiety ( r  = 0.30, P  =   0.01) and coping ( r  = 0.31, P  =   0.009) were significantly related with pain threshold.
Conclusions  In this study, two-thirds of IBS patients exhibited rectal hypersensitivity. No significant correlation was found between rectal threshold and either symptom intensity or alteration in QoL.     

Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome

AIM: To investigate the efficacy and safety of renzapride, a potent 5-hydroxytryptamine type-4 receptor full agonist and 5-hydroxytryptamine type-3 receptor antagonist in patients with constipation-predominant irritable bowel syndrome. METHODS: In this dose-escalating pilot study, 17 patients with constipation-predominant irritable bowel syndrome received placebo, renzapride 2 mg o.d. and renzapride 2 mg b.d. sequentially for 28 days. Response was determined by radio-opaque marker measurement of overall gastrointestinal and segmental colonic transit and patients' assessment of their irritable bowel syndrome symptoms. RESULTS: Renzapride reduced mean overall gastrointestinal transit time (placebo, 2.9 +/- 1.6 days; renzapride 2 mg o.d., 2.6 +/- 1.4 days; renzapride 2 mg b.d., 1.9 +/- 1.6 days) (P = 0.024) and accelerated segmental colonic transit, with statistically significant differences for renzapride 2 mg b.d. over placebo in caecum/ascending colon (P = 0.019) and descending colon (P = 0.022). Renzapride also reduced abdominal pain, increased the number of pain-free days and improved stool consistency. The frequency of reported adverse events was similar on renzapride and placebo. CONCLUSIONS: Renzapride is well-tolerated, stimulates gastrointestinal transit and improves symptoms in patients with constipation-predominant irritable bowel syndrome, particularly at the 2 mg b.d. dose, where improvements in gastrointestinal symptoms were evident over placebo. This study has established proof of concept and supports further investigation of renzapride in patients with constipation-predominant irritable bowel syndrome.     

Anti-hyperalgesic effect of octreotide in patients with irritable bowel syndrome

BACKGROUND: Octreotide has been found to be beneficial in the treatment of chronic pain, although the mechanisms underlying its therapeutic effect are incompletely understood. AIMS: To assess the effect of octreotide on perceptual responses to rectal distension in irritable bowel syndrome patients and healthy controls at baseline and following the experimental induction of rectal hyperalgesia. METHODS: In study 1, rectal perception thresholds for discomfort were determined in seven irritable bowel syndrome patients and eight healthy controls on three separate days using a computer-controlled barostat. Subjects received saline, low-dose and high-dose octreotide in a random double-blind fashion. In study 2, perceptual responses to rectal distension were obtained in nine irritable bowel syndrome patients and seven controls before and after repetitive high-pressure mechanical sigmoid stimulation. RESULTS: Octreotide increased the discomfort thresholds in irritable bowel syndrome patients, but not in controls, without changing rectal compliance. Repetitive sigmoid stimulation resulted in decreased rectal discomfort thresholds in the patient group only. In irritable bowel syndrome patients, octreotide prevented the sensitizing effect of repetitive sigmoid stimulation on rectal discomfort thresholds. CONCLUSIONS: Octreotide effectively increased discomfort thresholds in irritable bowel syndrome patients, but not in controls, at baseline and during experimentally induced rectal hyperalgesia. These findings suggest that octreotide exerts primarily an anti-hyperalgesic rather than analgesic effect on visceral perception.