Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome

The effect of granisetron, a specific 5-hydroxytryptamine 3-receptor antagonist, on the anorectal responses to rectal distension and a 1000-calorie meal was assessed in 12 patients with irritable bowel syndrome. Each patient was studied on three occasions, receiving intravenously either 40 mcg/kg granisetron, 160 mcg/kg granisetron or normal saline. Granisetron caused a dose-dependent reduction in rectal sensitivity, manifested by an increase in the threshold volumes at which the sensations of gas, desire to defecate, urgency and discomfort were perceived. This reached significance for all sensations at the higher dose level (P < 0.01). No significant changes in anal pressures, rectal compliance or distension-induced motor activity occurred following drug administration. A dose-dependent reduction in post-prandial motility was observed following intravenous granisetron and this was highly significant at 160 mcg/kg (P= 0.005). These results suggest that the 5 hydroxytryptamine receptor antagonists may have a therapeutic role in patients with irritable bowel syndrome.     

The effects of the 5-hydroxytryptamine (5HT3) receptor antagonist ICS 205-930 in the carcinoid syndrome

Therapy for diarrhoea associated with the carcinoid syndrome is often unsatisfactory. In an open study ICS 205-930 (Sandoz Limited), a novel 5HT3-antagonist, controlled diarrhoea in five of six patients studied. This drug may be a useful advance in the symptomatic treatment of the carcinoid syndrome.     

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.     

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.     

Review article: the therapeutic potential of 5-HT3 receptor antagonists in the treatment of irritable bowel syndrome

There is evidence from studies, in both animals and humans, that 5-HT₃ receptor blockade has potential value in the treatment of irritable bowel syndrome, particularly in those patients with diarrhoea-predominant bowel habits. New findings suggest that 5-HT₃ receptors exist on gut afferent neurones and that their activation by locally released 5-HT leads to visceral nociceptive stimulation, in addition to increased neuronally-mediated motor and secretory activity. If this concept is validated, it will provide a rationale for the use of 5-HT₃ receptor antagonists in patients with increased gut motility, reduced fluid absorption and low nociceptive thresholds leading to abdominal pain.
Alosetron is a highly selective, potent 5-HT₃ receptor antagonist which is well absorbed with a long pharmacodynamic half-life. Its ability to provide long-lasting blockade of 5-HT₃ receptors throughout the body make it an ideal candidate within its class to evaluate the clinical hypothesis that sustained and ubiquitous 5-HT₃ receptor blockade is of value in the treatment of IBS.     

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.     

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.     

Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist

BACKGROUND: No currently available treatment provides consistent relief of irritable bowel syndrome. Colonic sensory and motor function are modulated partly through 5HT3-receptors. AIM: To evaluate effects of the 5HT3-receptor antagonist, alosetron, in irritable bowel syndrome. METHODS: Randomized, double-blind, placebo-controlled, dose-ranging (1, 2, 4, 8 mg b.d. alosetron), 12-week trial in 370 patients with diarrhoea-predominant or alternating constipation and diarrhoea irritable bowel syndrome. Weekly measurement of adequate relief was the key end-point; other irritable bowel syndrome symptoms were collected daily using an electronic phone system. RESULTS: Alosetron (1 mg or 2 mg b.d.) significantly (P < 0.05 vs. placebo) increased the proportion of females, but not males, reporting adequate relief. Stool consistency, frequency and percentage days with urgency improved over placebo (P < 0.05) within the first month with all doses of alosetron, and persisted throughout the trial with all doses in female patients. With 1 mg b.d. alosetron, females had improved stool consistency and urgency within the first week, and adequate relief and improved stool frequency within the first 2 weeks. There was no consistent improvement in bowel function among male patients. CONCLUSION: In female irritable bowel syndrome patients with predominant diarrhoea or alternating constipation and diarrhoea, alosetron is effective in treatment of abdominal pain and discomfort and bowel-related symptoms.     

Targeting the 5-HT(3) receptor in the treatment of irritable bowel syndrome

Irritable bowel syndrome, which affects 5-10% of the population includes around 25% with predominantly diarrhoea (IBS-D). Several lines of evidence suggest an increase in mucosal 5-HT availability in IBS-D including a decrease in the serotonin transporter (SERT) which is also seen following acute diverticulitis. 5-HT(3) receptor antagonists have proved effective in suppressing urgency, prolonging small and large bowel transit and relieving symptoms in IBS-D. Alosetron continues to be used under restricted availability without any serious morbidity despite ischemic colitis which occurs at a rate of <1/1000 patient year. Other agents such as ramosetron and ondansetron are still in use and have not been associated with ischemic colitis. 5-HT(3) receptor agonists stimulate intestinal motility, shorten transit times and in a pilot trial accelerated transit in patients with IBS-C.     

Review article: the safety and efficacy of alosetron, a 5-HT3 receptor antagonist, in female irritable bowel syndrome patients

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal-related conditions. In this review, the safety and efficacy of alosetron, a potent and selective 5-HT₃ receptor antagonist, in the treatment of IBS are discussed.
Alosetron has been shown to produce statistically significant improvements in abdominal pain, stool consistency, stool frequency and urgency in female IBS patients. By contrast, no consistent improvement has been seen in male IBS patients treated with alosetron. The only adverse event of note with alosetron was constipation, and this represents a class effect of 5-HT₃ receptor antagonists.
In conclusion, alosetron is a safe and effective treatment for female IBS patients.     

Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study

Background  Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50–70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5-HT₃R antagonist alosetron is correlated with reduced amygdala activity.
Aim  To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with alosetron.
Methods  Basal psychological distress and neural activity (¹⁵O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of alosetron treatment.
Results  Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre-treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala.
Conclusions  Irritable bowel disease symptom improvement with 5-HT₃R antagonist alosetron is related to pre-treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome.     

Effect of sumatriptan, a new selective 5HT1-like agonist, on liquid gastric emptying in man

Paired studies were carried out on 12 healthy male subjects to compare the effect of intravenous doses of the 5-HT1-like agonist sumatriptan (GR43175; 3 mg), 10 mg metoclopramide and saline control on the rate of gastric emptying of a radiolabelled liquid test-meal. Intravenous administration of metoclopramide accelerated gastric emptying by decreasing the lag period, while intravenous administration of sumatriptan delayed gastric emptying by increasing the lag period. The observation that sumatriptan causes a delay in gastric emptying in normal healthy volunteers, but relieves nausea and vomiting during migraine attacks, suggests that sumatriptan may be acting via a central mechanism to relieve symptoms of nausea and vomiting associated with migraine.     

The haemodynamic effects of subcutaneous sumatriptan, a 5HT1-receptor agonist

Aims Previous in vivo studies with sumatriptan, a 5HT₁-receptor agonist, have demonstrated vasopressor responses in the pulmonary and systemic arterial circulation. Pulmonary artery wedge pressure (PAWP) also increases after sumatriptan injection, raising the possibility of an additional venoconstrictive action or a negative inotropic effect. The mechanism for the rise in PAWP was investigated in the study.
Methods Ten patients undergoing diagnostic coronary arteriography underwent haemodynamic monitoring.
Results There was a significant rise ( P <0.05) in systemic and pulmonary arterial pressure and total systemic and pulmonary vascular resistance. There was a similar rise ( P <0.05) in PAWP and left ventricular end diastolic pressure (LVEDP). There was no change in cardiac output nor in peak rate of left ventricular pressure rise (dP/dt).
Conclusions The sumatriptan induced rise in PAWP and LVEDP appears consequent upon increased afterload although a negative inotropic effect cannot be excluded.     

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.     

Tegaserod: a new 5-HT(4) agonist in the treatment of irritable bowel syndrome

Tegaserod is a selective partial agonist acting on serotonergic type 4 receptors (5-HT(4)). Pharmacodynamic studies indicate that tegaserod is able to stimulate gut propulsion and secretion with a net prokinetic effect. In contrast to other 5-HT(4) agonists endowed with a complex pharmacological profile, tegaserod has a reliable prokinetic activity in the colon. Clinical trials show that tegaserod is effective and safe in the treatment of patients with irritable bowel syndrome. In particular, tegaserod relieves symptoms of abdominal pain, discomfort, abdominal bloating and constipation.     

Double-blind study of an α2 agonist in the treatment of irritable bowel syndrome

A double-blind crossover trial of the alpha 2 agonist lidamidine hydrochloride in 72 patients with irritable bowel syndrome is reported. Lidamidine was found to have no significant effect on frequency and severity of abdominal pain or abdominal bloating. It did cause a statistically significant reduction in frequency of defaecation (P = 0.005), but this was of a degree unlikely to be of clinical importance. Although alpha 2 agonists inhibit gastrointestinal motility in animals this study suggests that lidamidine hydrochloride does not have a useful therapeutic role in irritable bowel syndrome.     

Effects on the rat oxyntic mucosa of the histamine2-antagonist loxtidine and the H+, K+-ATPase inhibitor omepvazole

The present study examined whether histamine could affect the growth of the enterochromaffin-like (ECL) cell and the parietal cell. The effects of the unsurmountable histamine H2-receptor antagonist loxtidine (80 mg/kg) and the H+, K(+)-ATPase inhibitor omeprazole (100 mumol/kg) were compared in female Sprague-Dawley rats. Both drugs were given by gavage once daily for 3 months. Omeprazole induced a more pronounced and sustained hypergastrinaemia than loxtidine. In spite of marked hypergastrinaemia during most of the day, even in the loxtidine-treated rats, the weights of the stomach and oxyntic mucosa were elevated only in the omeprazole-treated rats. The ECL cell density was slightly higher in the loxtidine- than in the omeprazole-treated rats. Both treatments elevated the gastrin-stimulated histamine release from the vascularly perfused stomach. The parietal cell density was unaffected by omeprazole treatment, whereas it tended to be reduced in the loxtidine-treated rats. Simultaneous administration of loxtidine and omeprazole reduced the sustained hypergastrinaemia induced by omeprazole given alone. The present study may indicate that histamine inhibits the growth of the ECL cell, but further studies are needed to elucidate if histamine has any trophic effect on the parietal cells.     

抗抑郁剂在肠易激综合征治疗中的作用

目的：重点研究和探讨抗抑郁剂辅助治疗肠易激综合征治疗临床疗效与安全性。方法利用病例回顾性分析方法,将269例肠易激综合征患者的临床资料进行比较分析。将患者按照给药方法不同分配成实验组与对照组,其中对照组患者为130例行常规治疗方法。实验组患者139例在对照组患者的给药基础上加用抗抑郁剂。然后观察分析两组肠易激综合征患者治疗结果、复发率、不良反应、患者满意度等情况。以便更好的明了抗抑郁剂在肠易激综合征治疗中的作用。结果通过观察统计本院收治的269例肠易激综合征患者的临床资料。可以得出实验组的治疗有效率、患者满意度明显大于对照组,差异有统计学意义（P〈0.05）。与此同时,实验组的不良反应发生率与复发率明显低于对照组,两组间比较差异具有统计学意义（P〈0.05）。结论在肠易激综合征的治疗过程中,适当给以患者抗抑郁药能更很好的提高治疗效果。而且不会因为抗抑郁药的应用提高不良反应发生率。值得临床借鉴和推广。