Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?

BACKGROUND: Abnormalities of gut motility and visceral pain perception are both thought to be involved in the pathogenesis of irritable bowel syndrome and may be susceptible to modulation by drugs affecting the various 5-HT receptor subtypes. The aim of this study was to investigate the therapeutic potential of a 5-HT3 antagonist in irritable bowel syndrome. METHODS: Fifty patients with irritable bowel syndrome were treated with ondansetron, a highly selective 5-HT3 antagonist, in a double-blind, placebo-controlled cross-over study. In addition to assessing its effect on the classical symptoms of irritable bowel syndrome (abdominal pain, distension and disordered bowel habit) its effect on symptoms often seen in irritable bowel syndrome, but more commonly associated with functional dyspepsia, was also examined. RESULTS: Ondansetron reduced bowel frequency (P = 0.035) and improved stool consistency (P = 0.002) in diarrhoea predominant irritable bowel syndrome and did not cause a deterioration of bowel habit in constipation predominant subjects. No statistically significant improvement was seen for abdominal pain or distension, although those patients who did respond were approximately twice as likely to be taking ondansetron than placebo. It was also found that ondansetron significantly improved the upper gastrointestinal symptoms of post-prandial epigastric discomfort (P = 0.008), flatulence (P = 0.022) and heartburn (P = 0.003). CONCLUSION: The results of this study justify evaluation of the therapeutic potential of selective 5-HT antagonists in both functional dyspepsia and irritable bowel syndrome.

Stenting for choledocholithiasis: temporizing or therapeutic?

Maxton and colleagues report their experience using biliary endoprostheses for treatment of failed common bile duct stone clearance after sphincterotomy. Of 283 patients with choledocholithiasis referred to their tertiary facility, 85 failed to have their ducts cleared with the first ERCP. There were 21 male and 64 female subjects; mean age was 77.5 yr. Clinical presentations were jaundice (39), cholangitis (23), and biliary colic and/or abnormal liver blood tests in the remainder. The patients were characterized as "elderly and ill with either jaundice or cholangitis present in almost 75%." Follow-up data were obtained for all patients. ERCP was first performed using a duodenoscope with a 3.2-mm instrument channel. A 7-French double pigtail stent was placed in each of the 85 patients with retained stones. Subsequent ERCP were performed at 2- to 3-month intervals using a therapeutic duodenoscope (4.2-mm instrument channel). A second stent was placed if stones remained in the bile duct after repeated extraction attempts. Patients deemed too frail and elderly for frequent ERCP had their first stent left in place, with stent exchanges and attempts at stone extraction every 6-12 months. Mechanical lithotripsy was used in 23 patients, extracorporeal shock wave lithotripsy (ESWL) in 11, and dissolution therapy via nasobiliary catheter in 10. Acute illnesses resolved in 84 of 85 patients, with significant decreases in bilirubin and alkaline phosphatase levels by the second ERCP. Six patients died with temporary stents in situ, one form a respiratory arrest the day of ERCP; the other deaths were unrelated to ERCP or choledocholithiasis. Fifty of the remaining 79 patients had successful stone clearance; 68% of these required two ERCP, 20% three ERCP, 6% four ERCP, and, in another 6%, a total of five ERCP were required before their ducts were free of stones. Seven cases of cholangitis among these 50 patients were treated successfully with i.v. antibiotics, fluids, and "early" stent replacement. Twenty-six patients had long term biliary drainage with the original stents in situ over 12 months. Four of these patients were among the six deaths, all unrelated to biliary stones or ERCP. Three patients were referred for surgical stone removal. The authors conclude that placement of a single 7-French stent after failure to clear common duct stones is safe, provides affective biliary drainage, can prevent the need for urgent surgical intervention, and allows for transfer of sick patients to centers of expertise. Further attempts at bile duct clearance were successful in most cases.

Retained common bile duct stones after endoscopic sphincterotomy: temporary and longterm treatment with biliary stenting.

Basket extraction after endoscopic sphincterotomy failed to clear the bile ducts immediately in 85 (30%) of 283 consecutive patients with common bile duct stones. Temporary biliary drainage was established by the insertion of a single 7 Fr double pigtail stent before further planned endoscopic attempts at stone removal. In 84 patients (21 male: 63 female, mean age 77 years) this measure relieved biliary obstruction, mean serum bilirubin falling from 101 to 18 umol/l by the time of the second endoscopic retrograde cholangiopancreatography. Six patients died from non-biliary causes with temporary stents in situ. Common bile duct stone extraction was achieved endoscopically in 50 of the remaining 79 patients after a mean of 4.3 months (range 1-12), 34 (68%) requiring only one further procedure. Three patients were referred for biliary surgery. Single stents were also effective for longterm biliary drainage in the remaining 26 elderly patients with unextractable stones. The main biliary complication of stenting was 13 episodes of cholangitis but all except one responded to medical treatment and early stent exchange. If common bile duct stones remain after endoscopic sphincterotomy, a single 7 Fr double pigtail stent is effective and safe for temporary biliary drainage before further endoscopic attempts at duct clearance and for longterm biliary drainage especially in the old and frail.

Absorption of iron from ferric hydroxypyranone complexes.

The absorption of 59Fe from preparations of FeSO4 and the ferric hydroxypyranone complexes maltol and ethyl maltol was studied by whole-body counting in normal subjects and patients with Fe deficiency. Fe in the Fe3+ complexes was in general absorbed almost as well as Fe2+. It is concluded that the absorption of Fe3+ from hydroxypyranone complexes is much greater than that from simple Fe3+ salts; this may prove an efficient and less toxic form of Fe for the treatment of deficiency.

Physiological effects of emotion: assessment via hypnosis.

Assessment of the physiological effects of physical and emotional stress has been hampered by a lack of suitable laboratory techniques. Since hypnosis can be used safely to induce specific emotional states of considerable intensity, we studied the effect on distal colonic motility of three hypnotically induced emotions (excitement, anger, and happiness) in 18 patients aged 20-48 years with irritable bowel syndrome. Colonic motility index was reduced by hypnosis on its own (mean change 19.1; 95% CI 0.8, 37.3; p less than 0.05) and this change was accompanied by decreases in both pulse (12; 8, 15) and respiration (6; 4, 8) rates (p less than 0.001 for both). Anger and excitement increased the colonic motility index (50.8; 29.4, 72.2; and 30.4; 8.9, 51.9, respectively; p less than 0.01 for both), pulse rate (26; 22, 30; and 28; 24, 32; p less than 0.001 for both), and respiration rate (14; 12, 16; and 12; 10, 14; p less than 0.001 for both). Happiness further reduced colonic motility although not significantly from that observed during hypnosis alone. Changes in motility were mainly due to alterations in rate than in amplitude of contractions. Our results indicate that hypnosis may help in the investigation of the effects of emotion on physiological functions; this approach could be useful outside the gastrointestinal system. Our observation that hypnosis strikingly reduces fasting colonic motility may partly explain the beneficial effects of this form of therapy in functional bowel disorders.

Functional bowel symptoms in diabetes--the role of autonomic neuropathy.

The autonomic nervous system may have a role in the pathogenesis of irritable bowel syndrome. If so, the occurrence of irritable bowel symptomatology in patients with autonomic neuropathy might indicate which, if any, of these symptoms are dependent on autonomic innervation. The prevalence of abdominal pain, abdominal distension and an abnormal bowel habit was recorded in 200 patients with diabetes, screened for autonomic neuropathy, and 200 matched controls. Constipation was significantly more common in patients with autonomic neuropathy than in those without, or controls (22.0% vs 9.2% vs 6.8%). The prevalence of abdominal pain and abdominal distension was no different in patients with and without autonomic neuropathy and their respective controls. The results of this study suggest that control of bowel habit is more dependent on the total integrity of the autonomic nervous system than the perception of pain or the production of distension.

More accurate diagnosis of irritable bowel syndrome by the use of 'non-colonic' symptomatology.

The criteria now used in an attempt to distinguish irritable bowel syndrome from organic gastrointestinal disease rely almost entirely on symptoms of colonic origin. 'Non-colonic' symptoms, however, arising either from elsewhere in the gut or of a more general nature, are common in irritable bowel syndrome and may have even better diagnostic potential. The prevalence of these non-colonic features was assessed in 107 patients with the irritable bowel syndrome and 295 subjects with other gut disorders. Gastrointestinal type non-colonic symptoms are useful in differentiating irritable bowel syndrome from inflammatory bowel disease but, with the exception of early satiety, are not helpful when there is gastro-oesophageal or biliary disease. More general 'non-colonic' features, such as lethargy and backache, are much commoner in irritable bowel syndrome than in all the organic gastrointestinal diseases studied and have good discriminant function. Multiple logistic regression analysis identified certain features that had a particularly significant independent risk for irritable bowel syndrome. Those were lethargy (relative risk 6.7), incomplete evacuation (RR 5.2), age under 40 (RR 2.1), backache (RR 2.0), early satiety (RR 1.8), and frequency of micturition (RR 1.8). These relative risks can be multiplied together to give an overall risk when more than one of these features is present in a patient. Until a diagnostic test is available more confident diagnosis of irritable bowel syndrome can be achieved by identifying symptoms that have good discriminant function. The results of this study indicate that the non-colonic features of irritable bowel syndrome may be especially valuable in this respect.

Abdominal distension in female patients with irritable bowel syndrome: exploration of possible mechanisms.

Abdominal distension is a common but little understood symptom of the irritable bowel syndrome. The authenticity of the symptom was confirmed by appreciable increases in girth measurement during the day in 20 patients with the irritable bowel syndrome compared with 20 control subjects. Objective corroboration of this finding was shown in the group with the irritable bowel syndrome by a highly significant increase in lateral abdominal 'profile' on computed tomography. Previously postulated mechanisms for distension--namely, retention of gas, depression of the diaphragm, and excess lumbar lordosis--were excluded by the radiological findings. Voluntary protrusion of the abdomen produced a completely different pattern on computed tomography to that observed in the irritable bowel syndrome. These observations suggest that abdominal distension may be related to changes in motility or tone of gastrointestinal smooth muscle.

Effect of hyperventilation on distal colonic motility and rectal sensitivity in irritable bowel syndrome.

Hyperventilation is associated with some symptoms suggestive of irritable bowel syndrome and has been implicated in provoking excessive oesophageal contractility. Sixteen patients with irritable bowel syndrome were therefore studied in order to assess the effect of hyperventilation on distal colonic motility and rectal sensitivity. No significant change in either the amplitude or frequency of colonic contractile activity was noted following hyperventilation, nor was any alteration in rectal sensitivity observed. This study shows that acute hyperventilation does not affect colonic motor activity or visceral sensitivity and suggests that hyperventilation and irritable bowel syndrome are not causally related.

Do non-steroidal anti-inflammatory drugs or smoking predispose to Helicobacter pylori infection?

Susceptibility to Helicobacter pylori infection is a poorly understood phenomenon. This study was undertaken to establish whether either smoking or chronic non-steroidal anti-inflammatory drug (NSAID) consumption might in some way predispose to H. pylori infection and hence lead to peptic ulceration. Serological evidence of H. pylori infection was assessed in 100 consecutive subjects receiving NSAIDs without any evidence of gastrointestinal upset and 100 matched controls. All subjects had a full assessment of their smoking habits. Sixty-three per cent of patients taking NSAIDs compared to 51% of controls had evidence of H. pylori infection (NS). Smoking habit also had no effect on H. pylori colonization. The ulcerogenic potential of NSAIDs and smoking does not appear to be mediated via a prediposition to H. pylori infection.

Effect of intra-colonic nicardipine on colonic motility in irritable bowel syndrome.

Intravenous nicardipine has previously been shown to abolish the effect of a 1000-calorie meal on colonic motility. The purpose of this study was to use the same experimental design to assess the effect of nicardipine instilled directly into the colon. Each patient was studied three times when receiving either placebo, 15 mg or 30 mg nicardipine infused over 2 h. Blood concentrations of nicardipine remained very low, but neither dose of the drug affected either basal or post-prandial colonic motility. Topical nicardipine does not appear to have therapeutic potential and its activity is probably dependent on systemic absorption.

Combined assessment of intestinal disaccharidases in congenital asucrasia by differential urinary disaccharide excretion.

Investigation of intestinal disaccharide hydrolysis and permeability by means of a non-invasive differential sugar absorption test was performed in a family containing two siblings with primary sucrase-isomaltase deficiency. The procedure, which depends on measurement of urinary excretion ratios after the oral administration of lactose, sucrose, palatinose, lactulose and L-rhamnose, is capable of simultaneous determination of intestinal lactase, sucrase, and isomaltase activity and lactulose:rhamnose permeability. The results corresponded well with those of disaccharidase assay and histological findings in jejunal biopsy tissue obtained from the patients. Palatinose proved a satisfactory substrate for in vivo assessment of intestinal isomaltase activity. The method described provides a reliable and comprehensive assessment of intestinal disaccharide hydrolysis, and simultaneous estimation of permeability assists discrimination of primary from secondary disaccharidase deficiency. The ability to assess three different disaccharidase activities in addition to intestinal permeability by means of a single test, and the simplicity of preservation and transport of urine samples for sugar analysis, makes this a convenient, definitive method for the investigation of defective sugar absorption in both patients and population groups.

Guide wire distance marks for oesophageal dilatation.

The addition of chemically etched distance marks to standard oesophageal guide wires is described so that guide wire retraction during progressive oesophageal dilatation and impending impaction of the dilator onto the flexible wire tip can be quickly and easily recognised.

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).

Controlled trial of pyrogastrone and cimetidine in the treatment of reflux oesophagitis.

Eighty patients with reflux oesophagitis were randomised to receive either Pyrogastrone five tablets daily or cimetidine 400 mg twice daily for six weeks, extended to 12 if necessary. At six weeks, 49% of the Pyrogastrone treated subjects and 37% of the cimetidine treated subjects were healed. After 12 weeks the cumulative healing rates were 64% for Pyrogastrone and 66% for cimetidine. Compared with baseline both drugs achieved similarly significant improvements in symptom score, endoscopic and histological grading even in those who did not heal completely. Response was not related to length of symptoms or initial severity of oesophagitis. Eleven of 25 (44%) patients healed with Pyrogastrone relapsed within one year compared with 15 of 27 (56%) healed with cimetidine. Although this trend in favour of Pyrogastrone was not significant at one year the early relapse rate was significantly greater in cimetidine treated subjects. At six weeks, five cimetidine treated subjects had relapsed compared with none in the Pyrogastrone group (p = 0.05). This study shows that Pyrogastrone and cimetidine are equally effective in the healing of oesophagitis and raises the possibility that Pyrogastrone has marginal benefits in terms of time to relapse.

Small-intestinal function during enteral feeding and starvation in man.

1. Small-intestinal absorption and permeability were measured in nine patients with malnutrition who were receiving liquid enteral nutrition after different periods of starvation, in five patients receiving enteral nutrition without starvation, in six healthy subjects after starvation for 36 h and in two obese subjects starved for 11 days. 2. Absorption, expressed by the plasma 60 min D-xylose level and the plasma 60 min D-xylose/3-O-methyl-D-glucose ratio, was greatly decreased (P less than 0.001) in the nine patients receiving enteral feeding after starvation, whereas permeability, denoted by the 5 h urinary lactulose/rhamnose ratio, was increased (P less than 0.05). 3. The five patients receiving enteral feeds without prior starvation had normal intestinal absorption and permeability. 4. Starvation of the healthy subjects reduced absorption (P less than 0.05) and this was detectable at 36 h. Permeability, however, was not increased by 36 h starvation. Starvation of the obese subjects also progressively reduced absorption, and this was reversed with refeeding. 5. Changes in intestinal function during enteral feeding are similar to those seen in intestinal diseases. They develop rapidly and are not caused or reversed by liquid enteral feeds. Starvation, before beginning feeding, may explain some of the changes found.

Effect of dietary fat on the small intestinal mucosa.

The presence of food within the small intestinal lumen promotes mucosal cell proliferation. To define the trophic role of triglycerides, three groups of eight female Wistar rats were isocalorically fed for four weeks with either Vivonex, or Vivonex with 50% calorie substitution with an essential fatty acid mixture, or Vivonex with 50% calorie substitution with a saturated fatty acid mixture. Although Vivonex caused greater body weight gain, both essential fatty acids and saturated fatty acids increased small intestinal weight, mucosal weight, protein and DNA overall, and in each of three intestinal segments (proximal, middle and distal), compared with Vivonex. Mucosal indices were similar for essential fatty acids and saturated fatty acids. These results show that triglycerides, regardless of essential fatty acid content, are trophic to the rat small intestinal mucosa.

Intestinal disaccharidases assessed in congenital asucrasia by differential urinary disaccharide excretion.

A patient with congenital asucrasia was investigated using in vivo differential urinary disaccharide excretion. Impaired hydrolysis of sucrose and isomaltose, but normal lactase activity, were demonstrated and confirmed by in vitro estimation. The technique of differential disaccharide excretion can now be used to assess three disaccharidases simultaneously, in vivo, including isomaltase.