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PubMed2004

Synthesis and pharmacological properties of benzamide derivatives as selective serotonin 4 receptor agonists.

A series of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamides with a polar substituent group at the 1-position of the piperidine ring was synthesized and evaluated for its effect on gastrointestinal motility. The benzoyl, phenylsulfonyl, and benzylsulfonyl derivatives accelerated gastric emptying and increased the frequency of defecation. One of them, 4-amino-N-[1-[3-(benzylsulfonyl)propyl]piperidin-4-ylmethyl]-5-chloro-2-methoxybenzamide (13a, Y-36912), was a selective 5-HT4 receptor agonist offering potential as a novel prokinetic with reduced side effects derived from 5-HT3- and dopamine D2 receptor-binding affinity. In the oral route of administration, this compound enhanced gastric emptying and defecation in mice, and has a possibility as a prokinetic agent, which is effective on both the upper and the lower gastrointestinal tract.

Animals↗
PubMed2001

Efficacy and tolerability of cisapride in children.

As gastro-oesophageal reflux disease (GORD) in infants and children is a motility disorder which differs in pathophysiology and clinical course from GORD in adults, prokinetics should be considered the drug of choice in certain circumstances. Indeed, cisapride may result in improvement of feeding tolerance in premature infants. Cisapride has a better tolerability profile than a 'wait-and-see-if-improvement-comes-spontaneously' policy or the other therapeutic options available. A careful and critical review of published data suggests that cisapride may have a QTc-prolonging effect. However, provided the precautions for cisapride administration are followed, the QTc-prolonging effect remains consistently without clinically relevant adverse effects. Correct dosage and avoidance of concurrent treatment with macrolides and/or azoles are the most relevant tolerability recommendations in children. Although there is a need for a prokinetic with better efficacy, cisapride is currently the prokinetic with the best benefit-to-risk ratio available. Thus, withdrawal of cisapride would result in a significantly increased risk for severe complications in infants and children with GORD or other gastrointestinal motility disorders such as chronic intestinal pseudo-obstruction, gastroparesis and feed intolerance in premature infants.

Child↗
PubMed2005

Chronic Intestinal Pseudo-Obstruction.

Chronic intestinal pseudo-obstruction (CIP) is a gastrointestinal motility disorder characterized by chronic symptoms and signs of bowel obstruction in the absence of a fixed, lumen-occluding lesion. Radiographic findings consist of dilated bowel with air-fluid levels. Pseudo-obstruction is an uncommon condition and can result from primary or secondary causes. The management is primarily focused on symptom control and nutritional support to prevent weight loss and malnutrition. The principles of management of patients with CIP involve 1) establishing a correct clinical diagnosis and excluding mechanical obstruction; 2) differentiating between idiopathic and secondary forms; 3) performing a symptomatic and physiologic assessment of the parts of the gastrointestinal (GI) tract involved by manometric and whole gut transit scintigraphic studies; 4) careful assessment of nutritional status of the patient; and 5) developing a therapeutic plan addressing the patient's symptoms and nutritional status. Treatment of CIP includes frequent small meals with a low-fat, low-fiber diet, liquid nutritional supplements may be needed; prokinetic agents such as metoclopramide may help to reduce upper GI symptoms. Trials of drugs such as erythromycin, domperidone, cisapride, and tegaserod may be considered if there is no response. Subcutaneous octreotide may be helpful to improve small bowel dysmotility especially in patients with scleroderma. In patients with symptoms suggestive of bacterial overgrowth, courses of antibiotics such as metronidazole, ciprofloxacin, and doxycycline may be needed. Nutritional assessment and support is an important aspect of management. Enteral nutrition is usually preferred. In carefully selected patients, feeding jejunostomy with or without decompression gastrostomy may be tried. Long term parenteral nutrition should be reserved for patients who can not tolerate enteral nutrition. Complications associated with total parenteral nutrition include infections, sepsis, and cholestatic hepatic dysfunction.

Journal Article↗
PubMed1986

Effects of somatostatin and SMS 201-995 on carbohydrate metabolism in normal man.

Growth hormone (GH) is important in diabetes in view of its anti-insulin actions and its relation to the long-term complications of the disease. The suppression of GH secretion in diabetics has theoretical and possible therapeutic interest. Native somatostatin has multiple actions, including inhibition of the secretion of insulin, glucagon, thyroid-stimulating hormone (TSH), and various gut hormones. It also has inhibitory effects on gastrointestinal motility, exocrine secretion, nutrient absorption, and splanchnic blood flow. Its therapeutic use is limited by a duration of effect of several minutes only. SMS 201-995 holds more potential than native somatostatin in view of its longer duration of action. Preliminary data suggest that 50 micrograms SMS 201-995 subcutaneously at night inhibits the nocturnal rise in GH secretion in normal man, but no effect on 24-h GH secretion is observed when SMS 201-995 is injected twice daily before meals. SMS 201-995 inhibits secretion of insulin, glucagon, and TSH in addition to growth hormone and induces carbohydrate intolerance when administered before food in normal subjects. Gastrointestinal side effects suggest additional effects on nutrient disposal, which are important when it is administered before food. Further studies are required to elucidate these effects of SMS 201-995 on endocrine and gastro-intestinal function in normal and diabetic man.

Carbohydrate Metabolism↗
PubMed1990

Influence of single and multiple doses of oral ranitidine on the gastric transit of an indigestible capsule in humans.

The effect of single and multiple doses of ranitidine on the gastric residence time of an indigestible pH-sensitive radiotelemetric device, the Heidelberg capsule, was evaluated in 12 healthy men (mean age, 29 +/- 8 years) in a placebo-controlled, randomized, crossover study. Each subject received 150 mg ranitidine or placebo orally 2 hours before administration of the Heidelberg capsule. A 500 kcal standardized breakfast was served 1/2 hour before the capsule was administered. Gastric pH was monitored at 15-minute intervals, until pyloric passage (pH increase greater than or equal to 3 U) of the Heidelberg capsule was observed. Blood samples (n = 12) were collected 0 to 8 hours after administration of drug or placebo. The subjects continued to receive ranitidine or placebo b.i.d. for 7 days and returned on day 8 for a similar evaluation. After a 1-week washout period, the subjects received the alternative treatment. The mean (+/- SD) gastric residence time of the Heidelberg capsule was significantly decreased after both single and multiple doses of ranitidine compared to placebo (3.1 +/- 0.9 versus 3.8 +/- 1.1 hours, p less than 0.02; and 2.9 +/- 0.74 versus 3.9 +/- 0.9 hours, p less than 0.005, n = 9). Gastric residence time was not determined in three subjects who showed unusually slow gastrointestinal motility after both placebo and ranitidine. Mean AUC(0-8 hr) and AUC(0-infinity) were significantly increased, whereas Cmax, tmax, and t1/2 remained unchanged after 7 days of ranitidine b.i.d. treatment. No ranitidine double-peak profile or linear pharmacokinetic-pharmacodynamic relationship was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2003

Increased prevalence of irritable bowel syndrome in patients with bronchial asthma.

Irritable bowel syndrome (IBS) is one of the most common diseases of the gastrointestinal tract. IBS may represent a primary disorder of gastrointestinal motility accompanied with motor dysfunction in various extraintestinal sites. Recent studies suggest that IBS is associated with bronchial hyper-responsiveness and bronchial asthma might be more prevalent in IBS patients than in control subjects. The aim of our study was to assess the prevalence of IBS in a cohort of asthmatic patients. We evaluated 150 patients with bronchial asthma (71 males and 79 females, aged 45.1+/-14.9 years) and two control groups including 130 patients with other pulmonary disorder and 120 healthy subjects. All subjects enrolled (asthmatic and controls) completed the Greek version of the Bowel Disease Questionnaire (BDQ). BDQ is a, previously validated, self-report instrument to measure gastrointestinal symptoms. Diagnosis of IBS was based on Rome II criteria. The IBS prevalence was significantly higher in asthmatics (62/150, 41.3%) than in subjects with other pulmonary disorders (29/130, 22.3%, P<0.001) and healthy ones (25/120, 20.8%, P<0.001). For all subjects studied, the prevalence of IBS was significantly higher in females (78/214, 36.4%) than in males (38/186, 20.4%, P<0.001). The IBS prevalence in asthmatic males was 29.5% vs. 15.2% in male patients with other pulmonary disorders (P=0.002) and 14.2% in male healthy subjects (P=0.002). The IBS prevalence in asthmatic females was 51.8% vs. 28.1% in females patients with other pulmonary disorders (P<0.001) and 26.5% in females healthy subjects (P<0.001). None of the asthma medications were associated with increased or decreased likelihood of IBS. We conclude that patients with bronchial asthma have an increased prevalence of IBS. Further studies are needed to clarify the potential pathogenetic mechanisms underlying the association between IBS and asthma.

Anti-Asthmatic Agents↗
PubMed2004

Pathophysiological significance of a reaction in mouse gastrointestinal tract associated with delayed-type hypersensitivity.

AIM: To explore the pathophysiological significance of delayed type hypersensitivity (DTH) reaction in mouse gastrointestinal tract induced by an allergen 2,4-dinitrochlorobenzene (DNCB). METHODS: BALB/c mice were randomly divided into control and DTH(1-6) groups. After sensitized by DNCB smeared on the abdominal skin, the mice were challenged with DNCB by gavage or enema. The weight, stool viscosity and hematochezia were observed and accumulated as disease active index (DAI) score; the gastrointestinal motility was represented by active charcoal propulsion rate; the colon pathological score was achieved by macropathology and HE staining of section prepared for microscopy; and the leukocyte migration inhibitory factor (LMIF) activity was determined by indirect capillary assay of the absorbance (A) of migrated leukocytes. RESULTS: Active charcoal propulsion rates of small intestine in the DNCB gavages groups were significantly higher than that in the control group (P<0.01). The DAI scores and pathological score in DNCB enema groups were also higher than that in the control group (P<0.05), and there were significant rises in LMIF activity in DNCB enema groups as compared with control groups (P<0.01). CONCLUSION: Mouse gastrointestinal DTH reaction could be induced by DNCB, which might facilitate the mechanism underlying the ulcerative colitis.

Animals↗
PubMed2007

Review article: fructose malabsorption and the bigger picture.

Fructose is found widely in the diet as a free hexose, as the disaccharide, sucrose and in a polymerized form (fructans). Free fructose has limited absorption in the small intestine, with up to one half of the population unable to completely absorb a load of 25 g. Average daily intake of fructose varies from 11 to 54 g around the world. Fructans are not hydrolysed or absorbed in the small intestine. The physiological consequences of their malabsorption include increasing osmotic load, providing substrate for rapid bacterial fermentation, changing gastrointestinal motility, promoting mucosal biofilm and altering the profile of bacteria. These effects are additive with other short-chain poorly absorbed carbohydrates such as sorbitol. The clinical significance of these events depends upon the response of the bowel to such changes; they have a higher chance of inducing symptoms in patients with functional gut disorders than asymptomatic subjects. Restricting dietary intake of free fructose and/or fructans may have durable symptomatic benefits in a high proportion of patients with functional gut disorders, but high quality evidence is lacking. It is proposed that confusion over the clinical relevance of fructose malabsorption may be reduced by regarding it not as an abnormality but as a physiological process offering an opportunity to improve functional gastrointestinal symptoms by dietary change.

Adolescent↗
PubMed2000

Projections from the central nucleus of the amygdala to the gastric related area of the dorsal vagal complex: a Phaseolus vulgaris-leucoagglutinin study in rat.

Electrophysiological and anatomic studies suggest that the amygdala regulates gastrointestinal motility and gastric acid secretion via projections to the dorsal vagal complex. The topography of these projections is poorly understood. Here, these projections were investigated by injecting anterograde tracer, Phaseolus vulgaris-leucoagglutinin, into the different divisions of the central nucleus of the amygdala in 13 rats. The distribution of immunohistochemically labeled terminals in the different portions of the dorsal vagal complex was analyzed. We found that (1) the dorsal aspect of the medial division of the central nucleus provided moderate projections to the dorsal vagal complex; (2) the heaviest projections terminated in the parvicellular and medial divisions of the nucleus of the solitary tract. These data suggest that via topographically organized projections, the amygdala can modulate the vago-vagal gastrointestinal reflexes in emotional and stressful situations.

Amygdala↗
PubMed2002

Molecular cloning of the rat proteinase-activated receptor 4 (PAR4).

BACKGROUND: The proteinase-activated receptor 4 (PAR4) is a G-protein-coupled receptor activated by proteases such as thrombin and trypsin. Although activation of PAR4 has been shown to modulate rat gastrointestinal motility, the rat PAR4 sequence was unknown until now. This study aimed to identify the rat PAR4 cDNA. RESULTS: The cDNA coding for the rat PAR4 homologue was cloned from the duodenum. Northern blots demonstrated a 3.0 kb transcript in the duodenum. Protein homology with mouse and human counterparts was 90% and 75% respectively. PAR4 is expressed predominantly in the esophagus, stomach, duodenum and the spleen. When expressed in COS cells, PAR4 is activated by trypsin (1 nM), thrombin (50 nM), mouse PAR4 specific peptide (500 microM) and a putative rat PAR4 specific activating peptide (100 microM), as measured by intracellular Ca2+-changes. CONCLUSIONS: We have identified and characterized cDNA encoding the rat PAR4 homologue. PAR4 is expressed predominantly in the upper gastrointestinal tract. It is activated by trypsin, thrombin and its newly identified rat PAR4 specific activating peptide.

Journal Article↗
PubMed1975

Diagnostic and therapeutic considerations for fecal impaction.

During an 18-month period, 18 patients were admitted to the Beth Israel Hospital because of fecal impaction or its complications. The records of the 18 patients were reviewed to determine the presenting signs and symptoms, radiologic findings, course and etiology of fecal impaction. Prior use of drugs that slow gastrointestinal motility was found in seven cases, and seven of the 18 patients had severe neuropsychiatric illness. The presenting signs and symptoms in almost all instances were consistent with a diagnosis of intestinal obstruction. The difficulty in differentiating intestinal obstruction caused by fecal impaction from obstruction resulting from other lesions is discussed. The diagnosis of fecal impaction should be entertained only after other causes of intestinal obstruction have been excluded.

Adolescent↗
PubMed1991

Gastric emptying and small bowel transit in male volunteers after i.m. ketorolac and morphine.

Ten male volunteers were studied in a randomized, double-blind crossover trial. Each received ketorolac tromethamine 30 mg and morphine sulphate 10 mg i.m. at an interval of 2 weeks. After a standard radiolabelled meal, gastric emptying half-time (GE) and small intestinal transit time (SIT) were measured using a gamma camera. Small intestinal transit time was measured also from end-tidal breath hydrogen (ETH), and overall gastrointestinal motility by time to first flatus (TFF). Mean GE, SIT and TFF were significantly prolonged by morphine compared with ketorolac (P less than 0.03); ETH was prolonged also, but the difference was not significant. There were no significant correlations between SIT, ETH and TFF. Most subjects reported adverse effects after morphine, but only one after ketorolac.

Adult↗
PubMed1993

Short-segment intestinal interposition of the distal esophagus.

Esophageal replacement remains a challenge. Colon and jejunum provide alternative conduits to replace the lower esophagus when stomach is not suitable. Between 1971 and 1991, 41 patients underwent short-segment interposition of the esophagus with jejunum or colon. Indications were failed antireflux procedures (n = 21), nondilatable stricture (n = 9), achalasia (n = 2), moniliasis (n = 2), Barrett's esophagus with carcinoma in situ (n = 2), hemorrhagic esophagitis after esophagogastrectomy (n = 1), motility disorder (n = 1), instrumental perforation (n = 1), carcinoma (n = 1), and leiomyosarcoma (n = 1). Thirty-one patients (75.6%) had prior surgical procedures. Interposition with colon was performed in 22 patients and with jejunum in 19. Major complications occurred in 45% after colon interposition (10/22) and hospital mortality was 4.5% (1/22). Major complications after jejunal interposition occurred in 31% (6/19) and hospital mortality was 10.5% (2/19). A contained anastomotic leak occurred in 1 patient, perforation of a colon segment in 1, and jejunal graft necrosis in a third. Late functional results in 34 patients with a mean follow-up of 87 months were excellent or good in 26, fair in 5, and poor in 1. Colon interposition failed to improve symptoms in 2 patients with gastrointestinal motility disorders. Six patients underwent manometry and barium food provocation study. Two colon segments and 3 jejunal interpositions were hypoperistaltic or aperistaltic according to manometry. There was 1 case of aperistaltic jejunum with a distended afferent loop. When stomach is not available, successful palliation of swallowing can be accomplished with either jejunum or colon. Surgeons involved in the management of esophageal disease should be familiar with the technical details of both procedures.

Adult↗
PubMed1983

Psychiatric illness and contraction abnormalities of the esophagus.

Over a six-month period 50 patients referred for clinical esophageal manometry were independently evaluated for psychiatric diagnoses to determine whether there was any association between psychiatric illness and esophageal motility disorders. The manometric studies were blindly classified according to findings in the esophageal body. Twenty-five patients were classified as having one or more of the following contraction abnormalities: an increase in mean wave amplitude, an increase in mean wave duration, an increased frequency of abnormal motor responses, or the presence of triple-peaked waves. Psychiatric diagnoses were made in 21 (84 per cent) of the 25 patients but in only 4 (31 per cent) of the 13 patients with normal manometric patterns (P less than 0.005) and 4 (33 per cent) of the 12 with other manometric abnormalities (P less than 0.01). The fact that psychiatric illness is associated with a specific cluster of esophageal contraction abnormalities may provide a basis for further investigation of the relation between emotional disturbances and disorders of gastrointestinal motility.

Adolescent↗
PubMed1999

Nutritional management of chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIP) is a gastrointestinal motility disturbance characterized by recurrent episodes of postprandial nausea and bloating in the absence of mechanical obstruction of the small bowel or colon. Weight loss and severe malnutrition are often seen in advanced stages of the disorder. This article discusses the nutritional management of patients with CIP, focusing on general dietary as well as enternal and parenternal nutritional support. Enteral access methods and various enteral formulas used in CIP are also discussed.

Chronic Disease↗
PubMed1994

Neural network for automatic analysis of motility data.

Continuous recording of intraluminal pressures for extended periods of time is currently regarded as a valuable method for detection of esophageal motor abnormalities. A subsequent automatic analysis of the resulting motility data relies on strict mathematical criteria for recognition of pressure events. Due to great variation in events, this method often fails to detect biologically relevant pressure variations. We have tried to develop a new concept for recognition of pressure events based on a neural network. Pressures were recorded for over 23 hours in 29 normal volunteers by means of a portable data recording system. A number of pressure events and non-events were selected from 9 recordings and used for training the network. The performance of the trained network was then verified on recordings from the remaining 20 volunteers. The accuracy and sensitivity of the two systems were comparable. However, the neural network recognized pressure peaks clearly generated by muscular activity that had escaped detection by the conventional program. In conclusion, we believe that neurocomputing has potential advantages for automatic analysis of gastrointestinal motility data.

Adult↗
PubMed2003

Streptozotocin-induced diabetes modulates presynaptic and postsynaptic function in the rat ileum.

Altered gastrointestinal motility frequently occurs in diabetic patients and also in animal models of diabetes but the underlying causes are not clear. In the present study, contractile responses to agonists and electrical field stimulation (EFS) and the inhibitory actions of an adenosine A(1) receptor agonist were investigated on ilea from 8-week streptozotocin (STZ)-induced diabetic rats. Contractile responses to carbachol, prostaglandin F(2 alpha) (PGF(2 alpha)), the calcium ionophore A23187 and to EFS were increased in diabetic tissues compared to controls. In contrast, the inhibitory effects of a potent and selective adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) on electrical field stimulation-evoked contractions were decreased in diabetic tissues compared to controls but its ability to relax carbachol-contracted tissues was unaltered. These results suggest that diabetes may cause alterations at both pre- and postsynaptic sites and this may lead in turn to the gastrointestinal complications seen in diabetic patients.

Animals↗