Effect of the kappa agonist fedotozine on perception of gastric distension in healthy humans

Background and Aim : Gastric hypersensitivity to mechanical distension has been observed in functional dyspepsia, but no drug is available that specifically acts on gastric afferent pathways to decrease gastric nociception. The aim of this study was to assess the effect of fedotozine, a synthetic ligand for peripheral kappa receptors, on human gastric sensitivity.
Methods : Twenty-seven healthy volunteers were randomized to receive either fedotozine (30 mg t.d.s.) or a placebo, for 7 days. On day 7, the effects of fedotozine were tested on discomfort threshold and gastric compliance during graded isobaric and isovolumic distensions. In 16 of these subjects, the effect of this drug was tested on somatic sensitivity. In 10 other healthy volunteers the effect of fedotozine on gastric distension-induced inhibition of the RIII reflex, a process closely related to visceral sensitivity, was also studied.
Results: During isobaric distensions, the discomfort threshold was significantly higher in subjects on fedotozine than in those on placebo (14.4±0.92 vs. 12.0±1.13 mmHg; P =0.04). Compared to placebo, fedotozine did not modify gastric compliance and somatic sensitivity. Fedotozine also reduced the inhibition of the RIII reflex induced by gastric distension.
Conclusion: Fedotozine decreases gastric sensitivity to distension by exerting specific action on gastric afferent pathways.     

Influence of tegaserod on proximal gastric tone and on the perception of gastric distension

BACKGROUND: Tegaserod, a 5-hydroxytryptamine-4 receptor agonist, enhances gastric emptying, but its effects on proximal stomach function have not been studied. AIM: To study the effect of tegaserod on gastric compliance, accommodation and perception of distension in humans. METHODS: Nineteen healthy volunteers (10 females; mean age, 23.9 years) were studied on three separate occasions after 7 days of treatment with placebo, tegaserod 2 mg b.d. or tegaserod 6 mg b.d. in a double-blind, randomized, three-way cross-over design. After the introduction of a barostat bag, stepwise distensions were performed to determine gastric compliance and sensitivity, and a mixed liquid meal was administered in isobaric mode to assess accommodation. RESULTS: Tegaserod had no effect on the pressures or volumes inducing first perception or discomfort. Tegaserod 6 mg b.d. enhanced fasting gastric compliance compared with placebo. Pre-prandial and post-prandial intra-balloon volumes were significantly higher after 6 mg b.d. than after placebo. Both tegaserod 2 and 6 mg b.d. shortened the time to maximum post-prandial intra-balloon volume. The amplitude of meal-induced gastric relaxation (post-prandial minus pre-prandial volumes) did not differ between the treatment arms. CONCLUSION: In humans, tegaserod allows for larger intra-balloon volumes both before and after a meal. These findings warrant the investigation of the therapeutic potential of tegaserod in dyspeptic patients with impaired accommodation.     

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.     

Prucalopride,a systemic enterokinetic,for the treatment of constipation

BACKGROUND: Laxatives are frequently ineffective in treating constipation. An alternative therapeutic approach is to target serotonin-4 receptors, which are involved in initiating peristalsis. AIM: In a double-blind, placebo-controlled trial, to assess the efficacy and safety of a systemically active serotonin-4 agonist, prucalopride. METHODS: Seventy-four women with constipation were stratified into slow or normal transit groups, and each group was randomized to receive either placebo or 1 mg prucalopride daily for 4 weeks. A bowel function diary was maintained. Whole-gut and orocaecal transit, visceral sensitivity, quality of life and psychological state were assessed before and after treatment. RESULTS: Prucalopride, not placebo, increased spontaneous stool frequency (P=0.008) and reduced time to first stool (P < 0.001). Prucalopride reduced the number of retained markers in all patients compared to placebo (P=0.004). Prucalopride reduced the mean number of retained markers in slow transit (P=0.069), but did not alter the marker count in normal transit (P=0.86). Orocaecal transit was accelerated by prucalopride, not placebo (P=0.004). Prucalopride, notplacebo, increased rectal sensitivity to distension (urge volume, P=0.01) and electrical stimulation (P=0.001). Prucalopride significantly improved several domains of the Short Form Health Status Survey and the disease-specific quality of life. Adverse effects were similar for prucalopride and placebo. CONCLUSIONS: Prucalopride improves symptoms, upper gut transit and gut sensitivity in constipated patients with both slow and normal transit. It improves transit in patients with slow transit. These changes are associated with improved well-being.     

Use of tegaserod along with polyethylene glycol electrolyte solution for colonoscopy bowel preparation: a prospective, randomized, double-blind, placebo-controlled study

BACKGROUND: Polyethylene glycol electrolyte solution (PEG-EL) used for colonoscopy preparation is not well tolerated by several patients. A significant number of patients have inadequate bowel preparation despite taking PEG-EL. AIMS: To determine the effect of prokinetic agent, tegaserod when given in addition to PEG-EL on patient tolerance, quality of colonic preparation and adverse side effects experienced. METHODS: In this prospective, randomized, placebo-controlled, double-blind study, a total of 130 patients scheduled for colonoscopy were enrolled. They were instructed to take three pills of either tegaserod 6 mg each or placebo (one pill twice on the day prior to and third pill in the morning on the day of colonoscopy) in addition to standard 4L of PEG-EL in the evening prior to the day of colonoscopy. Patient tolerance of preparation, quality of bowel preparation, overall satisfaction and adverse side effects were compared between the two groups. RESULTS: Fifty-five patients in placebo group and 58 patients in tegaserod group completed the study. There was no difference between the two groups in the tolerance of preparation, quality of bowel preparation, overall satisfaction and the side effects. CONCLUSION: Addition of tegaserod to polyethylene glycol electrolyte solution during colonoscopy preparation does not improve patient tolerance, quality of colonic preparation or the adverse side effects.     

Effect of asimadoline, a kappa opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity plays a major role in irritable bowel syndrome pathophysiology. Opioid kappa receptors on afferent nerves may modulate it and be the target for new irritable bowel syndrome treatments. AIM: This study evaluated the effect of the kappa opioid agonist asimadoline on perception of colonic distension and colonic compliance in irritable bowel syndrome patients. METHOD: Twenty irritable bowel syndrome female patients (Rome II criteria; 40 +/- 13 years) and hypersensitivity to colonic distension (Pain threshold < or = 32 mmHg) were included in a randomized double-blind cross-over trial comparing the effect of a single oral dose of asimadoline 0.5 mg or placebo on sensory thresholds (defined as a constant and sustained sensation) elicited by left colon phasic distension (5 mmHg steps, 5 min) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves. RESULTS: On asimadoline, pain threshold (mean +/- s.d.) (29.8 +/- 7.2 mmHg) was higher than on placebo (26.3 +/- 7.8 mmHg), difference not statistically significant (P = 0.1756, ANOVA). Area under curve of pain intensity rated at each distension step was significantly lower on asimadoline (89.3 +/- 33.9, ANOVA) than on placebo (108.1 +/- 29.7) (P = 0.0411). Thresholds of perception of nonpainful distensions were not altered on asimadoline, as compared with placebo. Colonic compliance was not different on placebo and asimadoline. CONCLUSION: Asimadoline decreases overall perception of pain over a wide range of pressure distension of the colon in irritable bowel syndrome patients, without altering its compliance. These data suggest that further studies should explore the potential benefit of asimadoline in treatment of pain in irritable bowel syndrome patients.     

Tegaserod: a review of its use in the management of irritable bowel syndrome with constipation in women

The treatment of irritable bowel syndrome with constipation (IBS-C) has historically been based on the severity of symptoms, with education, reassurance, dietary advice, bulking agents and laxative therapy offered as appropriate. Tegaserod (Zelnorm, Zelmac) is the first selective serotonin 5-HT(4) receptor partial agonist to be approved for the treatment of this syndrome. Tegaserod is active against multiple irritable bowel syndrome (IBS) symptoms; it stimulates gut motility and reduces visceral sensitivity and pain. The drug does not cure IBS and was not designed to treat the diarrhoea-predominant version. Its efficacy in men has not been established. Three large well designed clinical trials of tegaserod 6 mg twice daily for 12 weeks in patients (mainly women) with IBS-C have demonstrated superiority versus placebo in global relief from symptoms. Global relief response rates were 38.4-46.8% with tegaserod 6 mg twice daily and 28.3-38.8% with placebo (p < 0.05-0.0001 vs placebo). The relative increases in response rates with tegaserod 6 mg twice daily over the already high responses in the placebo groups ranged from 12-65% after 4-12 weeks of treatment. A response was seen within the first week. The proportion of patients with satisfactory relief from symptoms fell over the 4-week period following withdrawal of tegaserod and placebo, but did not reach baseline levels during this time. Diarrhoea has been associated with tegaserod in clinical trials (an incidence of about 10% versus 5% with placebo, usually occurring in the first week of treatment), but the drug is otherwise well tolerated. There were no apparent changes in the tolerability profile with extended tegaserod treatment (相似文献   

The effect of motilin on the rectum in healthy volunteers

AIMS: The role of motilin in the regulation of upper gastrointestinal (GI) motility is well defined. However, little is known about the effects on the distal GI tract. To investigate the effect of exogenous motilin on rectal function, barostat measurements in the rectum were performed and lower abdominal symptoms were scored. METHODS: Eight fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min in a double-blind, randomized, cross-over design. Rectum volume was measured with a barostat device during constant pressure and during isobaric distensions. Lower abdominal symptoms were scored by visual analogue scales. Plasma motilin concentrations were measured by radioimmunoassay. RESULTS: Baseline rectum volumes were similar between treatments: 185 +/- 62 mL (motilin) and 136 +/- 41 mL (placebo). During the constant pressure procedure, motilin increased rectum volume [area under the effect curve (AUEC)] by 6%[95% confidence interval (CI) -3, 16] of baseline, compared with placebo. During isobaric distensions motilin increased rectum volume (AUEC) by 43 mL (95% CI 0.4, 85; P < 0.05) and compliance by 10 mL mmHg-1 (95% CI 0.3, 20; P < 0.05) relative to placebo. Motilin did not induce changes in the sensation of rectal feelings. CONCLUSION: Exogenous motilin increased rectal compliance in healthy volunteers, without affecting rectal sensations.     

Double-blind, randomized, placebo-controlled study to evaluate the effects of tegaserod on gastric motor, sensory and myoelectric function in healthy volunteers

BACKGROUND: The effects of tegaserod on gastric accommodation and postprandial satiety remain unclear. AIM: To compare the effects of tegaserod 6 mg twice daily vs. placebo on gastric volumes, postprandial symptoms, gastric emptying, small bowel transit and the surface electrogastrogram in female and male healthy volunteers. METHODS: Randomized, double-blind, placebo-controlled study evaluated gastric function before and after 7 days of tegaserod 6 mg twice daily (n = 21) vs. placebo (n = 20) in healthy volunteers. Validated methods were used to study gastric emptying, myoelectrical activity, volumes and satiation postnutrient challenge. RESULTS: There were no significant effects of tegaserod on the primary endpoints assessing gastric function: emptying of solids or liquids, total gastric volumes or myoelectrical activity. Maximum tolerated volume and aggregate symptom score with nutrient challenge on placebo were 1,035 mL (+/-44) and 130 (+/-15) vs. 989 mL (+/-43) and 117 (+/-15) during tegaserod, respectively (all P = N.S.). Postprandial change in proximal gastric volume by single photon emission-computed tomography was decreased in females on tegaserod (246 +/- 30) vs. placebo (358 +/- 32) (P = 0.015). Proximal fasting volumes in females were increased on tegaserod (126 +/- 12) vs. placebo (92 +/- 13) (P = 0.066). CONCLUSIONS: While tegaserod decreased proximal gastric volume change after a meal, it does not appear to have significant effects on gastric motor and sensory function in healthy individuals. Further studies are required in patients with disturbances of gastric motor and sensory function.     

Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation

AIM: To investigate the efficacy and safety of tegaserod, a novel 5-HT(4) receptor partial agonist, in a randomized, double-blind, placebo-controlled, 12-week treatment, multicentre study. METHODS: Eight hundred and eighty-one patients with irritable bowel syndrome, characterized by abdominal pain, bloating and constipation, received tegaserod, 2 mg b.d. or 6 mg b.d., or placebo for 12 weeks. RESULTS: Tegaserod, 2 mg b.d. and 6 mg b.d., showed a statistically significant relief of overall irritable bowel syndrome symptoms, measured by a weekly, self-administered questionnaire. At end-point, treatment differences from placebo were 12.7% and 11.8% for 2 mg b.d. and 6 mg b.d., respectively. The effect of tegaserod was noted as early as week 1, and was sustained over the 12-week treatment period. Individual irritable bowel syndrome symptoms assessed daily also showed a statistically significant improvement of abdominal discomfort/pain, number of bowel movements and stool consistency, and a favourable trend for reducing days with significant bloating. Adverse events were similar in all groups, with transient diarrhoea being the only adverse event seen more frequently with tegaserod than placebo. CONCLUSIONS: Based upon the results of this study, tegaserod offers rapid and sustained relief of the abdominal pain and constipation associated with irritable bowel syndrome. Tegaserod is also well tolerated.     

Alosetron does not affect the visceral perception of gastric distension in healthy subjects

Background: The effect of alosetron, a new specific 5-HT₃, receptor antagonist, on the visceral perception in response to gastric distension was assessed in 12 healthy male subjects in a randomized, double-blind, placebo controlled crossover trial Methods: Each subject was given orally either alosetron 1 mg b.d. or placebo b.d. for 6 days (wash-out period 7–28 days). At the end of each dosing period, both isobarometric and isovolumetric gastric distensions were performed using an electronic barostat. Results: Alosetron did not modify the gastric wall compliance (pressure-volume relationship). Alosetron had an effect similar to placebo on the visceral perception scores in both isobarometric and isovolumetric distensions. The mean (± SEM) thresholds for abdominal discomfort were, respectively, 16.8 ±0.7 mmHg and 825 ± 61 mL with alosetron, 16.7±0.6 mmHg and 883±45 mL with Placebo (P = NS). Conclusions: 5-HT₃ receptors do not appear to be involved in the visceral perception of gastric distension in healthy subjects.     

Effect of a 5HT3-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome

In some patients with the irritable bowel syndrome, rectal urgency and discomfort are major clinical problems and, under experimental conditions, these symptoms are perceived at lesser volumes of rectal distension than they are in asymptomatic controls. Further, a 5-hydroxytryptamine type-3 receptor antagonist increased the threshold for rectal discomfort in irritable bowel syndrome. Our aims were, (a) to measure rectal sensation during isobaric distensions of the rectum, and (b) to test the effect of another selective 5HT₃ antagonist, ondansetron 0.15 mg/kg, on rectal sensitivity, colonic tone, rectal tone and manometric responses. Ten healthy volunteers and five patients with diarrhoea-predominant irritable bowel syndrome were studied. A multilumen barostatmanometric assembly was placed in the descending colon, and a second barostat balloon was positioned in the rectum. Tone in the wall of the colon and rectum was measured by the barostat balloon volume during a constant pressure clamp, while intraluminal pressures were recorded by manometry; perceived sensations were also recorded before and after the intravenous administration of ondansetron or placebo in blinded fashion. Rectal resistance to stretch was greater and rectal urgency was induced by lower distending pressures in irritable bowel syndrome, however, basal tone in the rectum was similar in health and irritable bowel syndrome. Ondansetron did not change rectal sensitivity (first sensation or urgency) or tone. Rectal distension did not alter tone in the descending colon or colonic manometry; ondansetron did not influence any index of colonic function. We conclude that in diarrhoea-predominant irritable bowel syndrome there is reduced rectal compliance and the rectum is abnormally sensitive to a pressure stimulus, but this is not altered by 5HT₃-blockade with ondansetron at the dose used.     

Influence of the selective serotonin re-uptake inhibitor,paroxetine, on gastric sensorimotor function in humans

BACKGROUND: The role of 5-hydroxytryptamine in the control of gastric fundus tone in humans is still unknown. Selective 5-hydroxytryptamine re-uptake inhibitors act both centrally and peripherally to enhance the availability of physiologically released 5-hydroxytryptamine. AIM: To study the influence of a selective 5-hydroxytryptamine re-uptake inhibitor, paroxetine, on gastric fundus tone, on the perception to gastric distension and on gastric accommodation to a meal. METHODS: Sixteen healthy volunteers underwent a gastric barostat study on two occasions, after pre-treatment with placebo or paroxetine, 20 mg/day. Graded isobaric and isovolumetric distensions were performed and perception was scored by a questionnaire. Subsequently, the amplitude of the gastric accommodation to a mixed liquid meal was also measured. RESULTS: Pre-treatment with paroxetine did not alter the thresholds for perception and discomfort during isobaric (4.7 +/- 2.3 vs. 4.0 +/- 2.0 mmHg and 13.3 +/- 3.1 vs. 12.7 +/- 2.3 mmHg above the minimum intragastric distending pressure, N.S.) and isovolumetric (307 +/- 90 vs. 417 +/- 114 mL and 772 +/- 74 vs. 750 +/- 76 mL, N.S.) distensions. Paroxetine significantly enhanced the amplitude of the meal-induced fundus relaxation (136 +/- 51 vs. 255 +/- 43 mL, P < 0.05). CONCLUSIONS: Pre-treatment with paroxetine enhances gastric accommodation to a meal. These data suggest that the release of 5-hydroxytryptamine, probably at the level of the enteric nervous system, is involved in the control of the accommodation reflex in humans, and that paroxetine may be beneficial to patients with impaired post-prandial fundus relaxation.     

Effects of nimesulide on nitric oxide-induced hyperalgesia in humans--a neurophysiological study

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to induce analgesia mainly via the inhibition of cyclo-oxygenase. Several reports suggest that chronic pain is mediated by central sensitization, an N-methyl-D-aspartate (NMDA)-mediated phenomenon influenced by cyclo-oxygenase activity and nitric oxide (NO). In this double-blind study, we evaluated the effects of a preferential inhibitor of the inducible isoform of cyclo-oxygenase-2, nimesulide, on the spinal nociceptive flexion reflex (RIII reflex) before and after administration of an NO donor in healthy volunteers. Nimesulide caused a reduction of the RIII reflex area, which persisted after NO donor administration. Conversely, in the placebo group the RIII reflex area significantly increased following the administration of the NO donor. These data suggest a central effect for nimesulide, possibly related to a reduction of nociceptive activity at spinal level.     

Effects of cholinergic agents on anorectal physiology

Background:

Despite their potential therapeutic benefit, the effects of cholinergic agents on anal function have been poorly investigated.

Aim:

To analyse the effects of neostigmine and atropine on anorectal responses to rectal isobaric distension.

Methods:

This was a placebo-controlled, randomized, double-blind crossover study, performed in 12 healthy volunteers who received intravenously, on 3 separate days, neostigmine, atropine or the placebo. During each day of the experiment, seven pressure steps (ranging from 1 to 31 mmHg) in three different protocols of rectal isobaric distension (phasic, stepwise and tonic) were applied using an electronic barostat. Manometric responses of the anal canal, adaptative volumes and perception scores of the rectum were recorded.

Results:

During stepwise distension, a significant drug effect was encountered at the anal level. No drug effect was observed on the other investigated parameters (rectal volumes and rectal perception scores) or for the other modes of distension. Compared to placebo, neostigmine significantly decreased pressures at the upper level of the anal canal for both recto anal inhibitory reflex and mean resting pressures. In contrast, atropine significantly increased pressures at the lower part of the anal canal but did not modify upper anal pressures.

Conclusion:

The present study suggests that cholinergic effects result more from an indirect action on intermediate neurotransmitters and rectal myenteric neurons, than from a direct action on anal targets.

     

Perioperative use of etoricoxib reduces pain and opioid side-effects after total abdominal hysterectomy: a double-blind, randomized, placebo-controlled phase III study

Abstract Objective: To evaluate the effects of two different doses of etoricoxib delivered perioperatively compared with placebo and standard pain management on pain at rest, pain with mobilization, and use of additional morphine/opioids postoperatively. Research design and methods: In this double-blind, placebo-controlled, randomized clinical trial, we evaluated postoperative pain following total abdominal hysterectomy over 5 days in patients receiving placebo or etoricoxib administered 90?min prior to surgery and continuing postoperatively. Patients were randomly assigned to receive either placebo (n?=?144), etoricoxib?90?mg/day (n?=?142), or etoricoxib 120?mg/day (n?=?144). Average Pain Intensity at Rest over days 1-3 (0- to 10-point numerical rating scale [NRS]) was the primary efficacy endpoint. Secondary endpoints included Average Pain Intensity upon Sitting, Standing, and Walking over days 1-3 (0- to 10-point NRS) as well as Average Total Daily Dose of Morphine over days 1-3. Clinical trial registration: This trial is registered on www.clinicaltrials.gov (NCT00788710). Results: The least squares (LS) means (95% CI) for the primary endpoint were 3.26 (2.96, 3.55); 2.46 (2.16, 2.76); and 2.40 (2.11, 2.69) for placebo, etoricoxib 90?mg, and etoricoxib 120?mg, respectively, significantly different for both etoricoxib doses versus placebo (p?相似文献   

A randomized,double-blind,placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation

BACKGROUND: Irritable bowel syndrome is a common functional gastrointestinal disorder which affects up to 20% of the population, with a predominance in females. AIM: To evaluate the efficacy and safety of tegaserod in female patients with irritable bowel syndrome characterized by symptoms of abdominal pain/discomfort and constipation. METHODS: In a randomized, double-blind, multicentre study, 1519 women received either tegaserod, 6 mg b.d. (n = 767), or placebo (n = 752) for 12 weeks, preceded by a 4-week baseline period without treatment and followed by a 4-week open withdrawal period. The primary efficacy evaluation was the patient's symptomatic response as measured by the Subject's Global Assessment of Relief. Other efficacy variables included abdominal pain/discomfort, bowel habits and bloating. RESULTS: Tegaserod produced significant (P < 0.05) improvements in the Subject's Global Assessment of Relief and other efficacy variables. These improvements were seen within the first week, and were maintained throughout the treatment period. After withdrawal of treatment, the symptoms rapidly returned. Overall, tegaserod was well tolerated. Diarrhoea was the most frequent adverse event; however, this led to discontinuation in only 1.6% of tegaserod-treated patients. CONCLUSIONS: Tegaserod, 6 mg b.d., produced rapid and sustained improvement of symptoms in female irritable bowel syndrome patients and was well tolerated.     

ANGIOTENSIN II BLUNTS, WHILE AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AUGMENTS, REFLEX SYMPATHETIC INHIBITION IN HUMANS*

1. The role of angiotensin (Ang)II in and the effects of angiotensin-converting enzyme (ACE) inhibitors on the regulation of sympathetic neural activity were examined in humans. 2. We measured baseline values of muscle sympathetic nerve activity (MSNA) and its reflex inhibition in 28 patients with essential hypertension with elevated plasma renin activity (PRA; > 1.0 ng/mL per h = 0.28 ng/L per s) before and after either acute or chronic oral administration of an ACE inhibitor or placebo and in 20 normotensive subjects before and after infusion of either AngII (5 ng/kg per min = 4.8 pmol/kg per min) or vehicle (5% dextrose). Muscle sympathetic nerve activity was recorded from the tibial nerve and its reflex inhibition was evaluated during pressor responses to bolus injection of phenylephrine (2 micrograms/kg, i.v.). 3. Blood pressure was significantly decreased (P < 0.01) after the acute oral administration of captopril (25 mg), accompanied by a slight increase in MSNA in patients with essential hypertension compared with control patients who received placebo administration. Reflex changes in MSNA were significantly augmented after oral administration of captopril (-4.1 +/- 0.5 vs -6.2 +/- 0.6%/mmHg, respectively; P < 0.01), with a significant reduction of plasma AngII, while they were not affected by placebo administration. 4. In contrast, acute AngII infusion was accompanied by decreases in both PRA and MSNA in normotensive subjects. Reflex changes in MSNA were significantly reduced after AngII infusion (-11.0 +/- 0.8 vs -7.4 +/- 1.0%/mmHg, respectively; P < 0.01) but not after vehicle alone. 5. Chronic ACE inhibition by 12 week oral imidapril administration (5-10 mg/day) significantly (P < 0.05) decreased baseline values of MSNA, which were accompanied by a significant (P < 0.05) increase in the reflex inhibition of MSNA, while plasma concentrations of noradrenaline were unaffected. 6. These results indicate that AngII blunts reflex inhibition of sympathetic neural activity and that inhibition of the renin-angiotensin system by an ACE inhibitor augments reflex regulation of sympathetic neural activity and reduces baseline values in patients with essential hypertension.     

Tegaserod in patients with mechanical sensitivity and overlapping symptoms of functional heartburn and functional dyspepsia

ABSTRACT

Background: While functional heartburn (FH) and functional dyspepsia (FD) are recognized clinical entities, symptoms often overlap across both disorders. Despite their frequency, little is known of the underlying pathophysiology of overlapping symptoms. This study evaluated the effect of the 5-HT₄ agonist, tegaserod, on visceral sensitivity and symptom improvement in patients with overlapping symptoms of FH and FD.

Research design and methods: Patients with overlapping symptoms of FH and FD (ROME II) and mechanical hypersensitivity (Barostat examination) were randomized to tegaserod 6?mg bid or placebo for 2 weeks with treatment crossover after a 2-week washout period. Esophageal and gastric Barostat sensory tests were performed and patients rated their overall symptoms at study end. When carry-over was detected, data were presented for period 1 only. Safety was also assessed.

Results: Sixty patients were screened of whom 30 were randomized and 25 completed. Mechanical hypersensitivity was reported by 83% of 47 patients completing esophageal and gastric baseline Barostat examinations. Tegaserod did not significantly alter balloon volume to pain (primary variable); however, pressure to gastric pain increased (p?=?0.044 vs. placebo). The severity of heartburn, regurgitation, early fullness, and bloating was significantly lower following tegaserod vs. placebo treatment (p?=?0.026, p?=?0.021, p?=?0.016, and p?=?0.030). Overall symptom improvement was reported by 52% tegaserod vs. 32% placebo patients (p?=?0.275), and treatment was well tolerated.

Conclusions: Results suggest that tegaserod may increase the gastric pain threshold and decrease the severity of individual symptoms in patients with overlapping FH and FD. However, these findings must be considered within the context of the study limitations, including the small number of subjects, potential for and presence of a carry-over effect, along with the impact of Barostat balloon use on the assessment of gastric function.