Effect of selective CCK1 receptor antagonism on accommodation and tolerance of intestinal gas in functional gut disorders.

BACKGROUND: Participants with functional gut disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. To determine the role of cholecystokinin (CCK1 ) receptors on gas transit and tolerance in women with functional gut disorders. METHODS: In 12 healthy women, and 24 women with functional gut disorders (12 dyspepsia and 12 constipation-predominant irritable bowel syndrome) gas was infused into the jejunum at 12 mL/min for 3 h with simultaneous duodenal lipid infusion (intralipid 1 kcal/min), while measuring anal gas evacuation and abdominal symptoms on a 0-6 score scale. Triple-blind paired studies during iv infusion of dexloxiglumide (2.5 mg/kg bolus plus 5 mg/kg h continuous infusion), a selective CCK1 inhibitor, or saline (control) were performed in random order. RESULTS: During saline infusion participants with functional gut disorders developed significantly greater gas retention and abdominal symptoms than healthy subjects (394 ± 40 mL vs 265 ± 35 mL and 2.8 ± 0.3 vs 1.9 ± 0.4 highest abdominal symptom score, respectively; P < 0.05 for both). Dexloxiglumide increased gas retention in both groups (514 ± 35 mL and 439 ± 60 mL, respectively; P = 0.033 vs saline for both); however, despite the larger retention, dexloxiglumide reduced abdominal symptoms (2.3 ± 0.2 score and 0.8 ± 0.3 score, respectively; P = 0.05 vs saline for both). Post-hoc analysis showed that, the decrease in abdominal symptoms was more pronounced in those participants with functional gut disorders with higher basal abdominal symptoms than in the rest (P = 0.037). CONCLUSION: Inhibition of CCK1 receptors by dexloxiglumide increases intestinal gas retention and reduces abdominal symptoms in response to by intestinal gas loads. European Clinical Trials Database (EudraCT 2005-003338-16).

Inulin-type prebiotics: a review. (Part 2).

This is part 2 of a two-part review of inulin-type prebiotics. This article discusses the clinical research on inulin-type prebiotics, including effects on infant nutrition, gastrointestinal health, colon cancer prevention, blood sugar and lipid metabolism, bone mineralization, fatty liver disease, obesity, and immunity. Gastrointestinal side effects and dosage recommendations are also considered.

Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake: implications for the pathophysiology of obesity.

The presence of fat in the small intestine slows gastric emptying, stimulates the release of many gastrointestinal hormones, and suppresses appetite and energy intake as a result of the digestion of fats into free fatty acids; the effects of free fatty acids are, in turn, dependent on their chain length. Given these effects of fat, it is paradoxical that high dietary fat intakes have been linked to increased energy intake and body weight and are considered to play a significant role in the pathogenesis of obesity. However, increasing evidence indicates that a chronic increase in dietary fat is associated with an attenuation of the feedback signals arising from the small intestine induced by fat, with a consequent relative acceleration of gastric emptying, modulation of gastrointestinal hormone secretion, and attenuation of the suppression of energy intake. This review addresses the gastrointestinal factors involved in the regulation of appetite and energy intake, with a particular focus on 1) the gastrointestinal mechanisms triggered by small intestinal fat that modulate energy intake, 2) the potential role of a high dietary fat intake in the development of obesity, and 3) implications for the prevention and management of obesity.

Novel opioid antagonists for opioid-induced bowel dysfunction and postoperative ileus.

Methylnaltrexone and alvimopan are two new and potentially useful agents in the management of opioid-induced bowel dysfunction and prevention of postoperative ileus. Both agents have promising prokinetic properties and appear to be capable of reversing the effects of opioids on delayed gastrointestinal transit. This article reviews currently available published literature to provide an overview of the clinical trials and to provide insight for the potential use of these agents for patients requiring opioid based analgesia. These compounds represent a new class of compounds that may impact the therapeutics for opioid induced bowel dysfunction as well as postoperative ileus.

[Clinical observation of slow transit constipation treated with acupuncture and modified weitong xiaopi formula].

OBJECTIVE: To compare the difference in the clinical therapeutic effects on slow transit constipation (STC) among the combined therapy of acupuncture and herbal medicine, simple use of herbal medicine and simple use of western medication. METHODS: Ninety patients of STC were randomized into three groups, 30 cases in each one. In the combined therapy group, acupuncture was used in combination with the modified weitong xiaopi formula. In the Chinese herbal medicine group, the modified weitong xiaopi formula was adopted. In the western medication group, mosapride citrate capsules were used. The duration of the treatment was 28 days. Before and after treatment, the colonic transit test was applied, the self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were selected for assessment. The clinical therapeutic effects were compared among the three groups. RESULTS: The total effective rate was 96.7% (29/30) in the combined therapy group, better than 90.0% (27/30) in the Chinese herbal medicine group and 76.7% (23/30) in the western medication group (P<0.05). In each group, before and after treatment, the residual marker amount was reduced apparently in the colonic transit test (all P<0.01). After treatment, the residual marker amount in the combined therapy group was less than that in the Chinese herbal medicine group (P<0.05) and that in the western medication group (P<0.01). The residual marker amount in the Chinese herbal medicine group was less than that in the western medication group (P<0.01). Compared with those before treatment, the scores of SAS and SDS were decreased in the combined therapy group and Chinese herbal medicine group (both P<0.01). After treatment, the scores of SAS and SDS in the combined therapy group were lower obviously than those in the other two groups (both P<0.01). CONCLUSIONS: Under the guidance of xuanfu theory, the combination of acupuncture and Chinese herbal medicine improve appa-rently colonic function and relieve the conditions of anxiety and depression in STC patients. The therapeutic effects are better than those treated with simple use of Chinese herbal medicine and simple use of western medication.

Short-chain fatty acids: ready for prime time?

The concept of colonic health has become a major target for the development of functional foods such as probiotics, prebiotics, and synbiotics. These bioactive agents have a profound effect on the composition of the microflora, as well as on the physiology of the colon, and display distinct health benefits. Dietary carbohydrates escaping digestion/absorption in the small bowel and prebiotics undergo fermentation in the colon and give rise to short-chain fatty acids (SCFA). As the main anions of the colon and the major source of energy for colonocytes, SCFA are rapidly absorbed by nonionic diffusion mostly but also by active transport mediated by a sodium-coupled transporter, thereby fostering the absorption of sodium and water. SCFA in general and butyrate in particular enhance the growth of lactobacilli and bifidobacteria and play a central role on the physiology and metabolism of the colon. The effect of prebiotics on cell proliferation, differentiation, apoptosis, mucin production, immune function, mineral absorption, lipid metabolism, and gastrointestinal (GI) peptides has been well documented experimentally. These effects seem to be largely mediated by SCFA, but evidence from human studies remains inconsistent. The food industry is making a leap of faith in their efforts to commercialize prebiotics and exploit potential health benefits. The future lies with the design of studies to further explore basic mechanisms, and gene expression in particular, but emphasis should be placed on human intervention trials.

Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial.

CONTEXT: Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing, and increased risk of valvular heart disease. Many patients respond to somatostatin analogs initially, but response diminishes in most patients. Additional options are needed. OBJECTIVE: To assess whether telotristat etiprate (TE) can reduce gastrointestinal symptoms in CS and reduce urinary 5-hydroxyindoleacetic acid (u5-HIAA; a biomarker of serotonin). DESIGN: A prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses. SETTING: A multicenter study. PATIENTS: Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use was allowed. INTERVENTIONS: TE, a novel oral inhibitor of peripheral serotonin synthesis. MAIN OUTCOME MEASURES: Primary: safety. Secondary: daily BMs, stool form, and u5-HIAA. RESULTS: Fifteen patients were enrolled, and 14 completed the treatment period. All patients experienced reductions in BMs per day (mean decrease, 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs per day. Nine patients (75%) reported "adequate relief" of gastrointestinal symptoms at 12 weeks, compared with two (17%) at baseline. Stool form and flushing also improved. Adverse events were mostly gastrointestinal (n = 10; 67%), consistent with underlying illness; three adverse events were serious (abdominal pain, diarrhea, and gastroenteritis) but were judged unrelated. CONCLUSION: TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with the mechanism of action of TE. These results support further evaluation in phase 3 studies.

New drugs in the management of the irritable bowel syndrome.

Irritable bowel syndrome (IBS) continues to provide a major therapeutic challenge to clinicians and those involved in drug development. It seems unlikely from the data before us that this multisymptom syndrome with peripheral and central components is likely to respond reliably in all patients to the same single agent. There is still a lack of well designed, appropriately powered, randomised clinical trials and the problems of dealing with the high placebo response rate in this group of patients remains a dilemma for trial designers. There are, however, some new ideas, particularly those relating to the role of hyperalgesia in IBS. For many patients, abdominal pain and bloating are the most distressing symptoms of this disease and the new drugs targeted at pain control, such as kappa agonists and serotonin antagonists (5-HT3) and possibly 5-HT4), may eventually find a place in the clinical management of this syndrome. Other candidates include somatostatin analogues and antidepressants, the latter predominantly for their effects on increasing pain threshold. More speculative new drugs for IBS include cholecystokinin antagonists such as loxiglumide and the gonadotrophin-releasing hormone analogue, leuprorelin (leuprolide). The results of on-going randomised clinical trials are still awaited for some of these newer agents. The irritable bowel syndrome (IBS) is the most common gastrointestinal condition encountered by general practitioners and is reported to account for up to 50% of the work of gastroenterologists in secondary care. However, most people with the symptoms of IBS (60 to 75%) do not consult a doctor. Its cause is unknown, its development is poorly understand and, perhaps not surprisingly, no universally agreed approach to treatment exists.

Systematic review: Antacids, H2-receptor antagonists, prokinetics, bismuth and sucralfate therapy for non-ulcer dyspepsia.

BACKGROUND: Evidence for the effectiveness of antacids, histamine-2 receptor antagonists, bismuth salts, sucralfate and prokinetic therapy in non-ulcer dyspepsia is conflicting. AIM: To conduct a systematic review evaluating these therapies in non-ulcer dyspepsia. METHODS: Electronic searches were performed using the Cochrane Controlled Trials Register, Medline, EMBASE, Cinahl and SIGLE until September 2002. Dyspepsia outcomes were dichotomized into cured/improved vs. same/worse. RESULTS: Prokinetics [14 trials, 1053 patients; relative risk reduction (RRR), 48%; 95% confidence interval (95% CI), 27-63%] and histamine-2 receptor antagonists (11 trials, 2164 patients; RRR, 22%; 95% CI, 7-35%) were significantly more effective than placebo. Bismuth salts (RRR, 40%; 95% CI, - 3% to 65%) were superior to placebo, but this was of marginal statistical significance. Antacids and sucralfate were not statistically significantly superior to placebo. A funnel plot suggested that the prokinetic and histamine-2 receptor antagonist results could be due to publication bias. CONCLUSIONS: The meta-analyses suggest that histamine-2 receptor antagonists and prokinetics are superior to placebo. These data are difficult to interpret, however, as funnel plot asymmetry suggests that the magnitude of the effect could be due to publication bias or other heterogeneity-related issues.

Effect of sun-dried raisins on bile acid excretion, intestinal transit time, and fecal weight: a dose-response study.

The effect of increasing doses of sun-dried raisins (SDR) on intestinal transit time (TT), fecal weight (FW), and fecal bile acids (FBA) was investigated in 16 healthy adults (6 men and 10 women). In three cycles of 2 weeks each, subjects consumed 84, 126, or 168 g/day of SDR. Four-day fecal collections were performed during the second week of each cycle, and TT, FW, and FBA were measured. FW (mean +/- SEM), increased from 168 +/- 14 g/day without raisins (cycle 1), with a TT of 54 +/- 6 hours, to 200 +/- 24 g/day with 168 g/day raisins (cycle 4), with a TT of 42 +/- 6 hours. Intermediate increases in FW and decreases in TT were observed for cycles 2 and 3. A physiologically meaningful decrease in TT (less than 2 days), to 44 +/- 6 hours, was reached at cycle 2 (not statistically significant). FBA, a possible indicator of colon cancer risk, showed a significant decrease, from 1.00 +/- 0.18 mg/g wet feces at baseline to 0.38 +/- 0.07 mg/g in cycle 2 (P <.005), and remained low in cycles 3 and 4. Major decreases were observed in cycle 2 for fecal lithocholic (P <.02), deoxycholic (P <.002), chenodeoxycholic, and cholic acids, and their concentrations remained low in cycles 3 and 4. Two servings of raisins per day (84 g/day), a relatively small change in diet, can cause beneficial changes in colon function and may decrease the risk for colon cancer.

Polyethylene glycol electrolyte solution (Isocolan) for constipation during pregnancy: an observational open-label study.

To evaluate the efficacy of a polyethylene glycol electrolyte solution (PEG-4000) in pregnant women affected by constipation, 40 consecutive pregnant women from 6 to 38 weeks' gestation were enrolled in this preliminary study. Constipation was defined as spontaneous evacuation less than four times a week or the presence of symptoms such as defecation pain, rectal urgency, tenesmus, anal injury, or abdominal pain. A PEG-4000 solution (Isocolan, also marketed in the United States as Golitely/Nulitely) was administered for 15 days at a dose of 250 mL by mouth once or twice a day. The number of bowel movements per week, the presence or absence of liquid stools, tenesmus, urgency, defecation pain, anal lesions, and abdominal pain were evaluated before and after 15 days of treatment. Treatment with PEG-4000 significantly increased the evacuation episodes per week (from 1.66 +/- 0.48 to 3.16 +/- 1.05; P <.01), and constipation was resolved in 27 of 37 women (73%). Defecation pain, anal injury, and abdominal pain significantly improved after PEG-4000 administration. Improvement occurred in both patients with new-onset constipation during pregnancy as well as patients with a history of constipation before pregnancy. These preliminary findings indicate that PEG-4000 may be an effective choice for the treatment of constipation during pregnancy.

Effect of lactulose and fiber-rich diets on bile in relation to gallstone disease: an update.

The primum movens in cholesterol gallstone formation is hepatic cholesterol hypersecretion and chronic supersaturation of bile. From this event a cascade of contributing factors can be differentiated: (i) Motility defects with impaired gallbladder contractility and gallbladder stasis, but also with small and large intestinal hypomotility. (ii) Multiple biochemical defects in gallbladder bile with increased biliary proteins, increased deoxycholic acid and rapid crystallization of biliary cholesterol from supersaturated unstable vesicles. There is considerable evidence that slow intestinal and colonic transit can increase the deoxycholic acid pool size and biliary cholesterol saturation. Changes in intestinal transit influence the anaerobic bacterial enzymatic biotransformation of conjugated cholate to more hydrophobic deoxycholate. This leads to biliary cholesterol hypersecretion and gallstone formation. Prokinetic drugs or administration of lactulose or fiber products like bran can change the slow intestinal transit favourably with subsequent reduction in deoxycholic acid formation and cholesterol saturation of bile. Whether these applications are indeed of value in the long-term prevention of gallstone disease, however, is doubtful, since fiber-rich diet in prevention of gallstone recurrence after complete gallstone dissolution was not successful.

[Ogilvie Syndrome induced by clozapine]. / Syndroom van Ogilvie als bijwerking van clozapine.

Clozapine is an antipsychotic drug which is used in the treatment of therapy-resistant schizophrenia. The most frequently reported side effects (occurring in more than 10% of patients) are gastro-intestinal complaints, including constipation. Here we describe the case of a 28-year-old man with schizophrenia who developed constipation and abdominal distension for several weeks while taking clozapine. He was admitted as an emergency suffering from clozapine-induced Ogilvie syndrome (acute pseudo-obstruction caused by a disturbed balance in the autonomic regulation of intestinal motility). Treatment on the intensive care unit was required because of septic shock and multiple organ dysfunction syndrome. Colonoscopy showed severe ischaemic colitis without signs of perforation or obstruction. Because conservative treatment with enemas, prokinetic drugs and antibiotics did not have sufficient effect, the cholinergic drug neostigmine was added to the treatment regimen. This led to a good clinical response, thereby averting the need for surgery. This case illustrates that decreased intestinal motility can be a severe problem for patients taking clozapine, which may lead to life-threatening complications.

Standardized concept for the treatment of gastrointestinal dysmotility in critically ill patients--current status and future options.

Inhibition of gastrointestinal motility is a major problem in critically ill patients. Motor stasis gives rise to subsequent complications including intolerance to enteral feeding, enhanced permeability of the atrophic intestinal mucosa and conditions as severe as systemic inflammatory response syndrome, sepsis and multiple organ failure. Although the diagnosis of motility disturbances in critically ill patients is difficult, the type and site of the disturbance are important to consider in the analysis of the condition and in the choice of therapeutic approach. The pharmacological treatment of impaired gastrointestinal motility is difficult to handle for the clinician, because the underlying mechanisms are complex and not fully understood and the availability of pharmacological treatment options is limited. In addition, there is a lack of controlled studies on which to build an evidence-based treatment concept for critically ill patients. Notwithstanding this situation, there has been remarkable progress in the understanding of the integrated regulation of gastrointestinal motility in health and disease. These advances, which largely relate to the organization of the enteric nervous system and its signaling mechanisms, enable the intensivist to develop a standardized concept for the use of prokinetic agents in the treatment of impaired gastrointestinal motility in critically ill patients.

Effects of therapeutic doses of lactulose vs. polyethylene glycol on isotopic colonic transit.

BACKGROUND: Lactulose and polyethylene glycol are osmotic agents used to treat idiopathic chronic constipation. AIM: To compare the effects of low doses of lactulose and PEG 4000 on transit time measured by scintigraphy in normal subjects. METHODS: For 5 days, 10 healthy subjects received either 10 g b.d. of lactulose or PEG 4000 in a randomized, double-blind, crossover study. On the evening of day 4, they took a capsule containing Amberlite resin pellets labelled with (111)In. On day 5, after a 1000 kcal test meal labelled with 99 Tcm, gastric, small bowel and colonic transits were measured. RESULTS: Gastric emptying and small bowel transit time were not different. Ascending colon emptying curve was significantly accelerated with lactulose in comparison with polyethylene glycol (P = 0.001) and, respectively, 50 +/- 18% vs. 35 +/- 18% of the radioactivity had left the ascending colon at the end of the study (P < 0.05). The descending colon filling curves, variations in the geometric centre and numbers of scintigraphic movements were not different. CONCLUSIONS: In healthy subjects, in comparison to PEG 4000, usual therapeutic doses of lactulose significantly accelerate ascending colon emptying. This result supports a stimulating motor effect of colonic fermentation of lactulose.

[Injection of botulinum toxin for diffuse esophageal spasm]. / Endoskopische Injektion von Botulinumtoxin A bei einem Patienten mit diffusem Osophagusspasmus.

HISTORY AND ADMISSION FINDINGS: A 67-year-old man complained of recurrent retrosternal pain for 3 - 5 minutes as the only symptom for 3 - 4 years. Only when dysphagia occurred in the course of the disease was a gastroenterologist consulted. INVESTIGATIONS: The diagnosis of diffuse esophageal spasm was confirmed by esophageal manometry and radiology. Upper gastrointestinal endoscopy revealed no further pathological findings. TREATMENT AND COURSE: 100 units of botulinum toxin were injected in 10 divided doses, into the tubular esophagus, 1 cm apart, beginning at the z-line of the gastroesophageal junction, deeply into the muscular coat of the posterior part of the esophageal wall. This achieved improvement of symptoms as well as esophageal transit time measured by scintigraphy. The symptomatic benefit has now lasted for several months. CONCLUSION: The treatment of patients with diffuse esophageal spasm with botulinum toxin is a promising therapeutic option, which can be safely performed in such patients. But this regime needs evaluation in controlled prospective clinical studies.

Mosapride citrate, a novel 5-HT4 agonist and partial 5-HT3 antagonist, ameliorates constipation in parkinsonian patients.

Mosapride citrate is a novel selective 5-HT4 receptor agonist. It facilitates acetylcholine release from the enteric cholinergic neurons. In contrast to cisapride, mosapride does not block K(+) channels or D2 dopaminergic receptors. The objective of this study is to perform an open study of mosapride citrate's effects on constipation, a prominent lower gastrointestinal tract disorder in parkinsonian patients. A total of 14 parkinsonian patients (7 with Parkinson's disease, 7 with multiple system atrophy; 10 men, 4 women; mean age, 67 years) with constipation (10 with bowel movement < 3 times/week; 14 with difficulty in defecation) were treated with 15 mg/day of mosapride citrate for 3 months. Pre- and posttreatment objective parameters in colonic transit time (CTT) and rectoanal videomanometry were obtained. Statistical analysis was made by Student's t test. Mosapride was well tolerated by all patients except for 1, who discontinued use of the drug because of epigastric discomfort. None had a worsening of parkinsonism or other adverse events. Thirteen patients reported subjective improvements in bowel frequency (>3 times/week, 13) and difficult defecation (13). Mosapride shortened CTT of the left colon (P < 0.01) and the total colon (P < 0.05). During rectal filling, mosapride lessened the first sensation (P < 0.05) and augmented the amplitude in phasic rectal contraction. During defecation, mosapride augmented the amplitude in rectal contraction (P < 0.05) and lessened the volume of postdefecation residuals. The present study showed for the first time that mosapride citrate augmented lower gastrointestinal tract motility, as shown in CTT and videomanometry, and thereby ameliorated constipation in parkinsonian patients without serious adverse effects.