Study with two prokinetics in functional dyspepsia and GORD: domperidone vs. cisapride.

The HT4-agonist Cisapride (CIS) and the peripheral D2-antagonist Domperidone (DOMP) have distinct prokinetic actions. We compared their clinical efficacy in 127 dyspeptic patients. Patients with upper abdominal complaints of > 1 month duration, who had a normal UGE were allocated to the REFLUX-group (RG), (predominance of heartburn, acid regurgitation or retrosternal pain) or if devoid of this specific symptomatology to the DYSPEPSIA-group (DG) In a double-blind randomised fashion and allocated to 10 mg CIS or 20 mg DOMP qid (RG) or tid (DG) for 1 month and followed-up for further 2 months. In RG (N = 43, p < 0.05) the response rates were clearly in favour of CIS, but not in DG (N = 84). In RG DOMP was more effective against nausea. The benefit of both therapies was largely maintained in the follow-up period. Cisapride and domperidone were effective in the treatment of dyspepsia. Cisapride was more effective than domperidone in the REFLUX-Group.

[Endoscopic findings in volunteers and dyspeptic patients]. / Endoskopische Befunde bei freiwilligen und dyspeptischen Patienten.

Although more than a fourth of the adult population reports dyspeptic complaints, little is known about the prevalence of clinically relevant UGI endoscopic findings in these patients in comparison with asymptomatic volunteers. This type of information is required in order to assess the relative risks of organic dyspepsia and the sensitivity and specificity of dyspeptic complaints for peptic lesions. In an attempt to fill this gap, the authors compared two trials carried out in the German-speaking part of Switzerland: (a.) 172 adult asymptomatic volunteers (age 20-78 years, 74 females, 98 males) participated in an epidemiological trial to measure the prevalence of positive CLO-urease tests and of upper GI-tract lesions. (b.) 119 patients (age 18-84 years; 68 females, 51 males) consulting their family doctor because of upper digestive symptoms of at least 1 month's duration (epigastric pain or discomfort, heartburn, acid regurgitation, early satiety, bloating, etc.) were referred for UGI endoscopy as a screening procedure; functional dyspeptics were thereafter randomized to a double blind drug trial (not reported here). In both trials the gastric presence of Helicobacter pylori was measured by means of the CLO-urease test. Prevalences of lesions and of positive urease-tests in the dyspeptic population were compared with the sex and age adjusted prevalences registered in the control population.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisapride or cimetidine in the treatment of functional dyspepsia. Results of a double-blind, randomized, Swiss multicentre study.

BACKGROUND: Functional dyspepsia is a major diagnostic and therapeutic challenge for the clinician. Several systems for the identification of 'high-risk' patients and classifications of dyspepsia subtypes and treatment schemes have been proposed in the past with limited experimental evidence to support the claims made. The present trial was designed to compare two different treatment modalities in a group of functional dyspepsia patients selected on the basis of a standardized diagnostic procedure as 'non-risk' for organic disease and to assess the result in the major symptom sub-groups of functional dyspepsia as a means of identifying the potential for improving treatment outcome. METHODS: The efficacy of the prokinetic drug cisapride (5 mg four times daily) and of the histamine H2-receptor antagonist cimetidine (200 mg four times daily) were evaluated after 1 month of treatment and after a further follow-up of 1 month. Patients were randomized to the trial if they fulfilled the following criteria: 1) 'low-risk' symptoms or negative endoscopy findings, and 2) 2 weeks of single-blind antacid treatment did not provide satisfactory relief. For analysis patients were stratified into dyspepsia subtypes. RESULTS: One hundred and sixty-one patients entered the run-in period, and 137 patients were randomized to the study. At the end of 4 weeks' treatment a small but significant difference in favour of cisapride was found; this difference can mainly be accounted for by the significant difference found in the dysmotility-like subtype (83% improved with cisapride versus 59% with cimetidine). No significant differences could be detected between drugs in the other dyspepsia subtypes at the end of the treatment-or follow-up period. CONCLUSIONS: The study confirms the classification into dyspepsia-subtypes as a useful tool in selecting the most appropriate drug therapy.

[Gallbladder dyskinesia and manometry of Oddi's sphincter]. / Gallenblasendyskinesie und Manometrie des Sphinkter Oddi.

Sphincter of Oddi activity partly regulates bile flow into the small intestine. This regulation is mainly controlled by phasic contractions and basal tone of the sphincter, together with gallbladder contraction. Manometric studies of the sphincter have permitted a better understanding of its physiological role and implication in biliary dyskinesia symptoms. Motility abnormalities of Oddi's sphincter present classically as bouts of recurrent pain and/or idiopathic pancreatitis, that can be successfully cured by endoscopic sphincterotomy.

[Drugs and assessment of gastrointestinal motility]. / Pharmaka und gastrointestinale Motilitäts-Messung.

Any determination of gastrointestinal motility is based on two assumptions: (1) That the patient is examined in "physiological" conditions and (2) that the values measured truly reflect the parameter the investigator wishes to examine. A large array of very different drugs shares the ability to modify the digestive motility (i.e. gastrokinetics) or to alter the content of the digestive tube in such a way that it affects the outcome of some measurements (i.e. acid suppression leads to false results in ph-metry dependent methods). Therefore, it seems advisable to ask the patient whether he is taking any drug--including non prescription medications--and check if this substance or type of substances could affect the outcome of the motility measurement envisioned. In this paper, the authors present a list of the principal drugs known to affect different motility-measurement methods. The real or apparent stimulating or inhibitory effects of drugs on four main segments of the digestive tube (esophagus, stomach, small intestines and colon) are indicated in an alphabetically ordered table. In a short review, the drugs are broadly classified according to their mechanism and site of action. Besides a number of drugs used in practice because of their action on the enteric nervous system, there is a large spectrum of compounds affecting motility, whose main therapeutic application lies outside the digestive tract, such as: psychotropic drugs, antiparkinsonian drugs, bronchodilators, antitussives, antihistamines, antimigraine drugs, antihypertensive agents, etc. This second category is more likely to escape unnoticed as a potential source of false results in the measurement of digestive motility.

[Constipation and incontinence: significance of colonic transit time, anorectal manometry and defecography]. / Constipation et incontinence: intérêt du temps de transit colique, de la manométrie ano-rectale et de la défécographie.

Constipation and fecal incontinence are frequent motives of gastroenterological consultation. An etiological diagnosis can often be suspected from the history and can be confirmed by functional testing. We here report our experience with the measurement of colonic transit time (TTC), anorectal manometry (MAR) and defecography (D). Whilst TTC was unhelpful, MAR revealed abdomino-pelvic asynchrony (anismus) in 60 constipated patients and 7 (47%) of 15 incontinent patients. Perineal descent was suspected in 25 constipated patients and confirmed by defecography, which also revealed associated static pelvic disorders. Our experience confirms the role of functional exploration in the investigation of constipation and fecal incontinence and permits a more precise therapeutic approach.

[Questionable usefulness of the edrophonium test in the diagnosis of non-cardiac retrosternal pain]. / Utilité discutable du test à l'édrophonium dans le diagnostic d'une douleur rétrosternale non cardiaque.

Of 69 patients with non-cardiac chest pain, one third had abnormal esophageal motility as evidenced by basal esophageal manometry. 8 patients (12%) reported chest pain during a provocation test (edrophonium). While this pain seemed similar to the spontaneous chest pain described by 7 patients, it was not associated with manometric changes in 30% of these cases. The causal relationship between disorders of esophageal motility and non-cardiac chest pain has still to be confirmed, and caution must be exercised in interpreting edrophonium tests.

[Endoscopic sclerotherapy and esophageal varices]. / Sclérose endoscopique et varices oesophagiennes.

60 consecutive patients underwent sclerotherapy for hemorrhage from ruptured esophageal varices. Sclerosis was always started within the first 48 hours. 12 patients (20%) died during initial hospitalization, but only 5 from recurrent bleeding. Of 48 survivors, 22 (46%) did not rebleed during a mean 18-month follow-up, whereas 26 (54%) had recurrences, 27 of these bleeding episodes occurred early (within 4 months) and 17 late (mean 16.5 months). Eradication of the varices was achieved in 29 patients (60%) with a mean of 6.2 sessions and within a mean of 6 months. Of these 48 patients 2 have been lost to follow-up, 25 (52%) are alive after a mean follow-up of 29 months, and 21 (44%) died (though only 2 from variceal bleeding). The survival curve (Kaplan-Meier) of these 60 bleeders is 45% and 37% at 2 and 4 years respectively. Sclerotherapy caused no death and only minor adverse effects. These results confirm those in the literature. We advocate endoscopic sclerosis as first choice in the treatment of ruptured esophageal varices.

Exocrine pancreatic nodules after longterm pancreaticobiliary diversion in rats. An effect of raised CCK plasma concentrations.

Surgical diversion of bile and pancreatic secretions to the mid small bowel has been shown to provoke increased CCK plasma concentration and growth of the pancreas in rats. This study was undertaken to investigate the effects of chronic pancreaticobiliary diversion on pancreatic morphology as well as the circulating concentrations of pancreatic polypeptide, secretin, gastrin, and CCK. Fifteen month diversion provoked 73 and 86% increases in pancreatic weight and volume (p less than 0.001). Cholecystokinin blood concentration increased by 98%, from 20.9 +/- 5.7 pg/ml in controls to 41.3 +/- 5.4 after diversion (p less than 0.05), but pancreatic polypeptide, secretin, and gastrin levels were not affected. The volume of the exocrine pancreas doubled from 1104.6 +/- 78.2 mm3 in controls to 2201.2 +/- 229.2 (p less than 0.001), with a matching increase in interstitial tissue. On the contrary, the volume of the endocrine pancreas remained unchanged. Hyperplastic nodules developed in the exocrine pancreas, in 71% of diverted rats, but not in transected controls. We conclude from these observations that chronic diversion of bile and pancreatic juice stimulated pancreatic growth, most likely through a persistent rise of CCK plasma concentrations. Furthermore, this long lasting stimulation induced the development of exocrine pancreatic nodules.

Idiopathic chronic watery diarrhea from excluded rectosigmoid with goblet cell hyperplasia cured by restoration of large bowel continuity.

A 73-year-old woman developed abnormal electrolyte and water loss from an excluded rectosigmoid segment after surgical treatment of a volvulus of the sigmoid colon. Rectal discharges lasted almost for a year, until it spontaneously resolved after restoration of large bowel continuity. Despite extensive investigation, including endoscopic, radiologic, microscopic, bacteriologic and parasitic examinations, no satisfactory explanation of the diarrhea could be found. The histologic pattern of the excluded segment showed a striking increase in mucosal thickness and in number and height of goblet cells. These abnormalities disappeared after closure of the colostomy. Electrolyte composition of the rectal fluid, which contained 134 mmol potassium and 22 mmol sodium per liter was remarkable and similar to that of normal stool water and anal discharges of patients with ulcerative proctitis.

[Potential adaptation of the gastrointestinal system. Existence of an enteropancreatic trophic axis, the role of hormones and polyamines]. / Potentiel d'adaptation du tractus gastro-intestinal. Existence d'un axe trophique entéro-pancréatique, rôle des hormones et polyamines.

The evidence for an enteropancreatic trophic axis is reviewed. Luminal nutrition is essential for the maintenance of normal intestinal mucosal, as well as exocrine pancreatic structure and function. Exclusion of luminal nutrition leads to mucosal hypoplasia and hypofunction with similar changes in the pancreas. The trophic effect of luminal nutrition may be mediated through the release of regulatory peptides with endocrine or paracrine effects. Enteroglucagon is the strongest candidate for the role of "enterotrophin" while cholecystokinin (CCK) markedly influences pancreatic growth. Thus, CCK not only stimulates exocrine pancreatic secretion but makes acinar cells divide and the pancreas grow. The cellular mechanisms whereby trophic peptides influence normal and adaptive growth are also discussed with emphasis on polyamines (putrescine, spermidine and spermine) and the key enzymes controlling their synthesis (ornithine decarboxylase [ODC]) and degradation (diamine oxidase [DAO]). When polyamine synthesis is blocked with the ODC inhibitor difluoromethyl ornithine (DFMO), the adaptive intestinal hyperplasia of pancreaticobiliary diversion is either inhibited or completely prevented. A proposed sequence of events might be: luminal nutrients, particularly long chain fat, reach the ileum and colon and stimulate increased enteroglucagon release. Enteroglucagon binds to cell receptors and triggers an intracellular cascade involving ODC and the polyamines which, in turn, stimulate RNA polymerase, DNA, RNA and protein synthesis, cell division and adaptive tissue growth.

Jejunal secretory effect of intraduodenal food in humans. A comparison of mixed nutrients, proteins, lipids, and carbohydrates.

The effect of the presence of food in the intestinal lumen on fluid transport by an intestinal loop isolated from nutrients is debatable and seems to be species dependent. The aim of the present study was to investigate this effect in humans. Fluid and ion transport by a 30-cm-long jejunal loop was measured by the perfusion of a plasmalike electrolyte solution below an occlusive balloon inflated at the angle of Treitz. At the same time, the duodenum was infused at the papilla by saline (control period) or one of the following solutions (test period): protein hydrolysate, starch hydrolysate, lipids, or mixed nutrients. The four solutions (pH 7; 300 mosmol/L; 540 kcal/L) were infused in 6 normal subjects in a randomized order. In 6 further subjects, two other loads of intraduodenal lipids (120 and 1080 kcal/L) were tested according to a similar protocol. Blood samples were taken serially for radioimmunoassays of gastrin, secretin, cholecystokinin, pancreatic polypeptide, gastric inhibitory polypeptide, vasoactive intestinal polypeptide, motilin, and somatostatin. Intraduodenal mixed nutrients, proteins, and lipids significantly reduced water and ion jejunal net absorption or induced a net secretion (without dose-effect relationship for lipids) and stimulated plasma cholecystokinin, pancreatic polypeptide, and gastric inhibitory polypeptide. Intraduodenal lipids also stimulated circulating levels of gastrin and vasoactive intestinal polypeptide. Intraduodenal sugars did not change jejunal fluid and ion transport and significantly increased plasma gastric inhibitory polypeptide. Covariance analysis showed transjejunal fluid movements to be linked with plasma levels of cholecystokinin. We conclude that an intraduodenal mixed meal exerts a secretory effect on a jejunal loop isolated from the nutrients and that this effect is due to the lipid and protein content of the meal; our data are compatible with a mediation of this phenomenon by cholecystokinin.

Hyperenteroglucagonaemia and small intestinal mucosal growth after colonic perfusion of glucose in rats.

Beside intraluminal factors, humoral agents play an important role in intestinal adaptation. Enteroglucagon, the mucosal concentration of which is maximal in the terminal ileum and colon, is the strongest candidate for the role of small intestinal mucosal growth factor. The present experiment was designed to study the role of colonic enteroglucagon in stimulating mucosal growth in rats with a normal small intestine. After eight days of glucose large bowel perfusion, enteroglucagon plasma concentrations were 120.7 +/- SEM 9.2 pmol/l, versus 60.1 +/- 6.8 in mannitol perfused control rats (p less than 0.001). Gastrin, cholecystokinin, neurotensin, pancreatic glucagon, and insulin plasma concentrations were unchanged. Crypt cell proliferation, measured by the vincristine metaphase arrest technique, increased significantly in the small intestine of glucose perfused animals (p less than 0.005-0.001) in comparison with the controls. This resulted in a greater mucosal mass in both proximal and distal small bowel: mucosal wet weight, DNA, protein and alpha D-glucosidase per unit length intestine were all significantly higher (p less than 0.05-0.001) than in mannitol perfused rats. Our data, therefore, support the hypothesis that enteroglucagon is an enterotrophic factor and stress the possible role of the colon in the regulation of small bowel trophicity.

Mechanism of pancreatic growth induced by pancreatico-biliary diversion in the rat. Inhibition by proglumide, benzotript, and ranitidine.

Pancreatico-biliary diversion (PBD) stimulates pancreatic growth in the rat. The present experiment was designed to investigate the mechanism of this phenomenon. The potential roles of endogenous CCK, gastrin, and secretin were studied. Hormone measurements by specific RIA's show that PBD was associated with higher CCK plasma concentrations and, conversely, with lower gastrin circulating levels. Secretin and pancreatic polypeptide were unaffected by PBD. Seven days' subcutaneous administration of proglumide (1000 mg/kg/day), benzotript (100 mg/kg/day), two CCK and gastrin receptor antagonists, and Ranitidine (100 mg/kg/day) resulted in a significant inhibition of PBD-induced pancreatic growth, assessed by measurements of pancreatic weight, DNA, RNA and protein content. These results suggest, therefore, that CCK plays a central role in the development of the pancreatic adaptive response to PBD.

Hormones and polyamines in intestinal and pancreatic adaptation.

The evidence for and against an enteropancreatic trophic axis is reviewed. Luminal nutrition is essential for the maintenance of normal intestinal mucosal, and exocrine pancreatic, structure and function. Exclusion of luminal nutrition leads to mucosal hypoplasia and hypofunction with similar changes in the pancreas. The trophic effect of luminal nutrition may be mediated through the release of regulatory peptides with endocrine or paracrine effects. Enteroglucagon is the strongest candidate for the role of 'enterotrophin' while cholecystokinin (CCK) markedly influences pancreatic growth. Thus, CCK not only stimulates exocrine pancreatic secretion but makes acinar cells divide and the pancreas grow. The cellular mechanisms whereby trophic peptides influence normal and adaptive growth are also discussed with emphasis on polyamines (putrescine, spermidine and spermine) and the key enzymes controlling their synthesis (ornithine decarboxylase; ODC) and degradation (diamine oxidase; DAO). When polyamine synthesis is blocked with the ODC inhibitor, difluoromethyl ornithine (DFMO), the adaptive intestinal hyperplasia of pancreatico-biliary diversion is either inhibited or completely prevented. A proposed sequence of events might be as follows: luminal nutrients, particularly long-chain fats, reach the ileum and colon and stimulate increased enteroglucagon release. Enteroglucagon binds to cell receptors and triggers an intracellular cascade involving ODC and the polyamines, which, in turn, stimulate RNA polymerase, DNA, RNA and protein synthesis, cell division, and adaptive tissue growth.