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Effects of magnesium citrate and clidinium bromide on the excretion of activated charcoal in normal subjects.

The efficacy of cathartics in shortening the gastrointestinal transit time of activate charcoal (AC) in the presence of drugs that alter gastrointestinal motility has not been determined. We evaluated the effects of magnesium citrate (MC) on the excretion of activated charcoal in healthy volunteers alone and with concurrent administration of the anticholinergic drug clidinium bromide. Forty subjects were randomized to clidinium bromide 5 mg or placebo capsule (PC), followed by activated charcoal 15 g and magnesium citrate or a placebo liquid (PL). The onset and duration of excretion of activated charcoal were noted. Mean onset times for activated charcoal were: group I (CB, MC) 4.5 +/- 2.1 h; group II (CB, PL) 17.0 +/- 10.0 h; group III (PC, MC) 6.3 +/- 5.8 h; and group IV (PC, PL) 20.6 +/- 8.4 h. The onset of excretion of activated charcoal was statistically different in both magnesium citrate groups as compared with the placebo liquid groups. The duration of activated charcoal in the stool was similar among the groups. The addition of clidinium bromide did not appear to affect gastrointestinal transit time. These results support previous studies of the effects of cathartics on the excretion of activated charcoal, and suggest that cathartic efficacy is not inhibited by anticholinergic drugs when used in therapeutic doses.

Adult↗

Nitric oxide impairs the 17beta-estradiol-induced apoptosis in human colon adenocarcinoma cells.

Nitric oxide (NO) and 17beta-estradiol (E2) are both important in gastrointestinal health and disease. NO contributes to gastrointestinal motility as well as to inflammation and carcinogenic processes. By contrast, E2 reduces the incidence of colon adenoma and carcinoma by about 30%. We report the genomic and non-genomic E2-estrogen receptor (ER) beta-induced effects in human colon adenocarcinoma. The effect of NO on ERbeta activities was also assessed. The E2-ERbeta-dependent gene transcription was inhibited by exogenous NO, whereas some non-genomic E2-dependent effects (e.g. p38/MAP kinase), important for the activation of the apoptotic cascade, were unaffected by NO. However, NO impaired the E2-induced pro-apoptotic cascade in human colon adenocarcinoma cells by inhibiting caspase-3. The effects of NO may reflect chemical modification(s) of Cys residues present in the DNA recognition domain of ERbeta as well as in the caspase-3 active site. On the whole, high NO concentrations suppressed the E2 protective effects in the gastrointestinal tract, suggesting that the caspase-dependent apoptotic cascade may become critical under conditions of high redox stress such as occur under specific activation of the immune system by chronic infections or pathogen challenge.

Adenocarcinoma↗

[Postoperative ileus: part II (Clinical therapy)].

To avoid or reduce postoperative ileus, the operative trauma should be minimized and epidural anesthesia for spinal inhibition of the sympathetic nervous system or i. v. lidocaine should be used, all of which probably act by reducing visceral afferent nerve fiber activity. Recent data suggest that perioperative fluid restriction might reduce postoperative ileus. Epidural anesthesia with local anesthetics and replacing opioids by non-steroidal anti-inflammatory drugs (NSAIDs) for postoperative pain treatment improve the recovery of gastrointestinal motility disturbances. Prior to the operation, the patient should be informed regarding postoperative motility disorders, its length and the presumed resumption of oral food intake, which has been shown to shorten hospital stay. Early postoperative food intake stimulates small and large bowel motility via interenteric reflex arches, avoids i. v. lines and renders discharge acceptable for the patient. Treatment of postoperative ileus includes osmotic laxatives and prokinetic drugs like erythromycine and acetylcholinesterase inhibitors. By combining epidural anesthesia and the sparse use of i. v. opioids with early food intake and, if necessary, laxatives or prokinetics, postoperative ileus should be coped adequately. Nevertheless, the development of new specific prokinetic drugs with minimal or no side effects should remain a target for drug companies to further improve treatment of postoperative ileus.

Afferent Pathways↗

Should cisapride be avoided in patients with diabetic gastroparesis?

The gastrointestinal motility stimulants, cisapride and erythromycin, have been used in the management of diabetic gastroparesis. However, drug interactions may result in prolongation of the electrocardiographic QT interval with the risk of ventricular arrhythmias. These drugs should, therefore, not be used in combination. We report two cases that illustrate inappropriate use of these agents. Moreover, patients with recurrent severe hypoglycemia or renal impairment may be at increased risk from cisapride-related cardiotoxicity. Thus, even as monotherapy, cisapride may pose dangers for high-risk diabetic patients.

Adult↗

Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact.

BACKGROUND: The impact of irritable bowel syndrome, a gastrointestinal motility disorder, is underestimated and poorly quantified, as clinicians may see only a minority of sufferers. AIM: To determine the prevalence, symptom patterns and impact of irritable bowel syndrome in the US. METHODS: This two-phase community survey used quota sampling and random-digit telephone dialing (screening interview) to identify individuals with medically diagnosed irritable bowel syndrome or individuals not formally diagnosed, but fulfilling irritable bowel syndrome diagnostic criteria (Manning, Rome I or II). Information on irritable bowel syndrome symptoms, general health status, lifestyle and impact of symptoms on individuals' lives was collected using in-depth follow-up interviews. Data were also collected for healthy controls identified in the screening interviews. RESULTS: The total prevalence of irritable bowel syndrome in 5009 screening interviews was 14.1% (medically diagnosed: 3.3%; undiagnosed, but meeting irritable bowel syndrome criteria: 10.8%). Abdominal pain/discomfort was the most common symptom prompting consultation. Most sufferers (74% medically diagnosed; 63% undiagnosed) reported alternating constipation and diarrhoea. Previously diagnosed gastrointestinal disorders occurred more often in sufferers than non-sufferers. Irritable bowel syndrome sufferers had more days off work (6.4 vs. 3.0) and days in bed, and reduced activities to a greater extent than non-sufferers. CONCLUSIONS: Most (76.6%) irritable bowel syndrome sufferers in the US are undiagnosed. Irritable bowel syndrome has a substantial impact on sufferers' well-being and health, with considerable socioeconomic consequences.

Activities of Daily Living↗

In utero defecation by the normal fetus: a radionuclide study in the rabbit.

An experimental study was performed to investigate the excretion function of the liver, gastrointestinal motility, and in utero defecation by radionuclide techniques in 24 New Zealand white rabbit fetuses at 25 days' gestation (fullterm, 31 to 32 days). 0.1 mL of technetium 99m (99mTc)-HIDA (a derivative of iminodiacetic acid) containing 1 mCi of radioactivity was injected into the gluteus muscle of each fetus which had been exposed through the uterus. After replacing the fetus and uterus into the abdomen, and beginning 1 hour after injection, a live fetus was killed each hour for 24 hours Tissue samples from the lung heart, stomach, kidney, bladder, liver, meconium in the proximal, mid and distal bowel, and amniotic fluid were taken. The radioactivity of each sample was determined by a gamma counter and the percentage uptake per gram of tissue was calculated. The very low radioactivity levels detected in the stomach, kidneys, and bladder indicated the in vivo stability of 99mTc-HIDA 99mTc-HIDA is predominantly trapped by the liver via systemic circulation and is excreted into the gastrointestinal tract through which it passes into the amniotic fluid. Demonstrated passage of excreted 99mTc-HIDA through the fetal liver and into the gastrointestinal tract and amniotic fluid strongly suggests that fetal defecation is a physiological event.

Amniotic Fluid↗

Loss of interstitial cells of cajal and inhibitory innervation in insulin-dependent diabetes.

BACKGROUND & AIMS: Gastrointestinal complications of long-standing diabetes include nausea, vomiting, abdominal pain, diarrhea, and constipation. The pathophysiology underlying these symptoms is poorly understood. Recent evidence suggests an important role for interstitial cells of Cajal in controlling gastrointestinal motility. The aim of this study was to determine changes in interstitial cells of Cajal and enteric innervation in a patient with insulin-dependent diabetes. METHODS: A full thickness jejunal biopsy was obtained from a 38-year-old insulin-dependent diabetic with evidence for diabetic gastroenteropathy. Immunohistochemistry, confocal microscopy, and 3-dimensional reconstruction techniques were used to quantify changes in the volume of interstitial cells of Cajal and enteric innervation. RESULTS: Interstitial cells of Cajal were markedly decreased throughout the entire thickness of the jejunum. A decrease in neuronal nitric oxide synthase, vasoactive intestinal peptide, PACAP, and tyrosine hydroxylase immunopositive nerve fibers was observed in circular muscle layer while substance P immunoreactivity was increased. CONCLUSIONS: The data suggest that long-standing diabetes is associated with a decrease in interstitial cells of Cajal volume and a decrease in inhibitory innervation, associated with an increase in excitatory innervation. The changes in interstitial cells of Cajal volume and enteric nerves may underlie the pathophysiology of gastrointestinal complications associated with diabetes and suggest future therapeutic targets.

Adult↗

[Gastric emptying in non-insulin dependent diabetic patients].

Disordered gastrointestinal motility is an often overlooked clinical problem. Delayed gastric emptying of solid and/or liquid meal in patients with both type 1 and type 2 diabetes mellitus occurs in approximately 50% of these patients. Gastric emptying time (GET) was studied in seventy four non-insulin dependent (type 2) diabetic out-patients by using radionuclide gamma-photography with Tc-99m phytate solid experimental meal. Thirty nine of them received Tc-99m phytate liquid test meal on the next day. Forty six normal healthy volunteers acted as controls. The results showed that solid GET in patients with type 2 diabetes mellitus was significantly delayed (149.44 +/- 64.0 min) as compared with that in the control group (88.7 +/- 14.2 min) (p < 0.001). Fifty three among these 74 diabetic patients had delayed solid GET, accounting for 71.6%. Only 5 of 39 (12.8%) diabetic patients showed delayed liquid GET (average 38.7 +/- 35.3 min; control 46.2 +/- 11.1 min). There were no differences in sugar control, duration of the disease, and upper gastrointestinal symptoms between patients with delayed GET and those with normal GET. We concluded that delayed gastric emptying is very common in patients with non-insulin dependent diabetes mellitus and which has no direct correlation to blood sugar control, duration of the disease, and upper gastrointestinal symptoms. Radionuclide solid gastric emptying test is a both safe (low radioactivity) and convenient (non-invasive) diagnostic tool in non-insulin dependent diabetic gastroparesis.

Adult↗

Potassium channel activation by cromakalim affects the slow wave type action potential of colonic smooth muscle.

The objective was to determine the existence of a glybenclamide-sensitive K+ conductance in intestinal smooth muscle, to study a possible role for this conductance in the generation of colonic slow wave type action potentials and to investigate if modification of this conductance could alter the action potentials and hence colonic motility. Intracellular electrical recording techniques were used to study properties of cells from the network of smooth muscle cells and interstitial cells of Cajal at the submucosal border of the circular muscle layer of the canine colon, where colonic pacemaker activity is generated. Cromakalim, dose dependently, hyperpolarized the cells and decreased the duration of the action potential, thereby inhibiting contractile activity. The upstroke amplitude and the action potential frequency remained unaltered. Glybenclamide did not affect any parameter of spontaneous electrical activity but prevented all effects of cromakalim. Cromakalim seems to act through increase in K+ conductance because the cromakalim-induced hyperpolarization is accompanied by a marked reduction in input resistance, is inhibited by glybenclamide and tetraethylammonium and it is shown that the cromakalim effect does not occur through effects on Na+ or Cl- conductances. Thus, glybenclamide-sensitive K+ conductance exists in colonic smooth muscle; the spontaneous development of slow wave type action potentials in this tissue occurs independent of this conductance. Its existence may provide pharmacological possibilities to affect gastrointestinal motility.

Action Potentials↗

Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (Part I).

Drug treatment of gastrointestinal diseases, which was previously limited to the use of antacids, anticholinergics, antispasmodics, cathartics and laxatives, has changed markedly over the past decade. Histamine H2-receptor antagonists (e.g. cimetidine, ranitidine and more recently famotidine and nizatidine) have revolutionised the treatment of peptic acid disorders, but their role is currently challenged by muscarinic-M1-receptor antagonists (e.g. pirenzepine), proton pump inhibitors (e.g. omeprazole), prostaglandin analogues and site-protective drugs (e.g. colloidal bismuth subcitrate and sucralfate). Newer antiemetics with prokinetic properties (e.g. metoclopramide, domperidone and cisapride) have also been introduced in the management of gastrointestinal motility disturbances, and new anti-inflammatory salicylates (e.g. olsalazine and mesalazine) have been developed for the treatment of chronic inflammatory bowel diseases. Finally, diphenoxylate and loperamide have gained wide clinical application as nonspecific antidiarrhoeal agents. The basic pharmacokinetic properties of the above agents are briefly reviewed with the main emphasis on the newer and more important drugs in current use. Furthermore, the effects of age and disease on pharmacokinetics, in addition to drug interaction potentials and pharmacokinetic-pharmacodynamic relationships, are discussed. The anti-inflammatory salicylates, nonspecific antidiarrhoeal agents, laxatives and cathartics will be dealt with in Part II.

Anti-Ulcer Agents↗

A disturbance of the gastric myoelectric activity in post-operative patients with biliary atresia.

BACKGROUND: Abnormalities in gastrointestinal motility have been reported in adult patients with advanced liver disease. However, there have so far been no reports on the gastric myoelectric activity in post-operative patients with biliary atresia (BA). AIM: The purpose of this study was to evaluate the gastric myoelectric activity in post-operative patients with BA in relation to liver fibrosis. PATIENTS AND METHODS: Twenty-one post-operative patients with BA, consisting of 6 boys and 15 girls with a mean age of 8.0 years and 6 healthy children (control group) were included in the study. The gastric myoelectric activity was measured by electrogastrography (EGG). The patients with BA were divided into two groups according to the serum hyaluronic acid (HA) level as a marker of liver fibrosis: the fibrotic group (FG, n=11), HA>50 ng/ml and the non-fibrotic group (NF, n=10), HA <==50 ng/ml. All recorded data were spectrally analyzed and any parameters related to changes in the dominant peak frequency (DPF) and its power were investigated. Furthermore, the gastrointestinal symptom scores (GSS) were calculated in patients with dyspeptic symptoms according to the degree of advanced liver fibrosis. RESULTS: The results showed that 1) the postprandial DPF in the FG tended to be higher than that in the NFG ( p=0.051), 2) the postprandial variability index of the DPF in the FG and NFG were significantly higher than those in the controls ( p<0.05), and 3) the preprandial percentage of normal waves (PNW) in the FG tended to be lower than that in the controls ( p=0.089). The postprandial PNWs in the FG and NFG were significantly lower than those in the controls ( p<0.05). Especially, the postprandial PNW in the FG was significantly lower than that in the NFG ( p<0.05). 4) The power ratio in the FG and NFG were significantly lower than those in the controls ( p<0.05), and 5) the GSSs in the FG were significantly higher than those in the NFG ( p<0.05). CONCLUSIONS: The gastric myoelectric activity appeared to be disturbed in BA patients associated with portal hypertension and neurohormonal changes due to liver fibrosis.

Adolescent↗

[Long QT interval and malignant ventricular arrhythmia during treatment with cisapride. Report of a clinical case].

Cisapride is largely used in the treatment of secondary symptoms due to gastroesophageal reflux, as a prokinetic drug that increases and coordinates gastrointestinal motility and gastroesophageal sphincteric tone. Potential proarrhythmic effects of the drug have been demonstrated in several clinical studies and reported by the drug manufacturers. These effects are increased in the presence of risk factors such as renal insufficiency, electrolytic disorders, coronary artery disease and positive history for arrhythmias including atrial fibrillation and bradyarrhythmia. Therefore in such cases a careful cardiac evaluation, both clinical and electrocardiographic, is recommended. This is still not routinely performed. The following case report shows an example in which diagnosis of increased QT interval due to cisapride was missed. This caused hospitalization for malignant ventricular arrhythmias and recurrent syncope.

Aged↗

Effects of motilin on human interdigestive gastrointestinal and gallbladder motility, and involvement of 5HT3 receptors.

A plasma motilin peak and a partial gallbladder emptying precede the antral phase III of the migrating motor complex (MMC). To clarify the causal relationship between these factors, we aimed to study the role of motilin in interdigestive gastrointestinal and gallbladder motility simultaneously. In addition, involvement of 5HT3 receptors in the action of motilin was studied. Eight fasting, healthy male volunteers received 13Leu-motilin or 0.9% NaCl i.v. for 30 min, in randomized order on two separate occasions, from 30 min after phase III. Seven of the eight subjects also received the 5HT3 receptor antagonist ondansetron in addition to motilin, on a third occasion. Antroduodenal motility, gallbladder volumes and plasma motilin were measured. The interval between the start of infusion and phase III was 95.0 (57.6-155.7) min for saline, 28.7 (21.0-33.2) min for motilin, and 39.3 (30.7-100.5) min for motilin + ondansetron (P < 0.05). Gallbladder volume decreased by one-third from 10 min after both motilin and motilin + ondansetron infusion (P < 0.05), and returned to baseline with duodenal passage of phase III. In two of the seven subjects phase III was absent after motilin + ondansetron, although gallbladder volume decreased and only refilled during a later spontaneous phase III. We conclude that motilin induces both partial gallbladder emptying and antral phase III. Indeed, although gallbladder emptying clearly precedes antral phase III, ondansetron only prevented phase III in some cases and had no effect on gallbladder emptying. Passage of phase III in the duodenum makes an important contribution to gallbladder refilling.

Adult↗

Bioavailability of fluconazole administered via a feeding tube in intensive care unit patients.

Fluconazole, a triazole compound with potent activity against many medically important fungi, undergoes rapid oral absorption, and has been shown in healthy volunteers to exhibit virtually complete bioavailability. The purpose of this study is to evaluate the bioavailability of fluconazole administered via a feeding tube with concomitant enteral feeds in intensive care unit patients. Once prescribed by the attending physician, fluconazole was administered either as an intravenous infusion over 1 h or the tablet was crushed and given via a feeding tube with concomitant enteral feeds. Once blood samples were obtained (not before the fifth dose) of the first regimen, the patient could be switched over to the alternate route and blood samples were again obtained after at least five doses. All patients had normal gastrointestinal motility, normal renal, and hepatic function. Serum concentrations were determined by a validated HPLC method. The area under concentration-time curve (AUC) was calculated using the trapezoidal rule; bioavailability was determined from the ratio of AUC(tube)/AUC(intravenous). The bioavailability for five patients was calculated to be 97.2 +/- 9.8%. Fluconazole retained excellent bioavailability when crushed and administered via a feeding tube with or without concomitant enteral feeding in critically ill patients. This alternative route of administration promotes cost savings and decreases the chance for secondary infection from indwelling intravenous catheters.

Adult↗

The gastrointestinal endocrine system.

Gastrointestinal endocrinology is the study of the hormonal regulation of digestion. A number of characterized polypeptide hormones have been localized in specific gastroenteropancreatic endocrine cells. The fact that some of these hormones are also found in nerve and brain cells has given rise to the concept of a gut-brain axis. The functional capacities of these endocrine cells are determined by their anatomic location; the luminal exposure of gastroenteric endocrine cells represents an additional avenue for stimulation and release that is not open to pancreatic endocrine cells. Gastroenteropancreatic hormones regulate carbohydrate metabolism, gastric acid secretion, pancreatic exocrine and gallbladder function, gastrointestinal motility and blood flow. These important regulatory hormones may in turn be controlled by a series of gastroduodenal releasing hormones.Diabetes mellitus is the most important metabolic disorder related to a gastroenteropancreatic hormone imbalance. Most tumours producing these hormones are of pancreatic origin and produce a number of hormones; insulinomas and gastrinomas are detected readily because of the serious metabolic distrubances they cause. Other instances of altered circulating concentrations of these hormones result from rather than cause the disease.The challenge of future study is to determine if postprandial changes in the plasma concentrations of these hormones are sufficient or necessary, or both, for the control of digestion.

Carbohydrate Metabolism↗

What is the essential role in the normalized rat intestinal transit? Calcium or calcitonin.

BACKGROUND/AIMS: Both calcium and calcitonin have been involved in mediating gastrointestinal motility. Using a thyroidectomized rat model the present study tried to determine which one of them was essential for normal small intestinal transit. METHODOLOGY: Adult Sprague-Dawley male rats simultaneously received thyroidectomy or a sham operation plus a laparotomy for duodenal tubing. After two-week housing, a small intestinal transit study was conducted via geometric center computation of radioactivities of the intestinal segments counted from intraduodenal feeding of radiochromium. Before feeding, these rats were i.p. injected with saline or human calcitonin in the doses of 0.1, 1 and 10 microM/kg, respectively. Another group of Tx rats received i.v. infusion of saline or CaCl2 for 30 min before motility study. RESULTS: Thyroidectomization effectively delayed transit compared to the sham-operated controls (3.59 +/- 0.15 vs. 2.98 +/- 0.32, P < 0.05). High doses of calcitonin treatment in thyroidectomized rats further inhibited transit (P < 0.01), whereas calcitonin did not restore the suppressed calcium level. Delayed transit in thyroidectomized rats was restored after calcium infusion (2.95 +/- 0.22 vs. 3.78 +/- 0.42, P < 0.05) while their hypocalcemia was already corrected. CONCLUSIONS: Thyroidectomization disturbs small intestinal transit, while peripheral calcitonin replacement further inhibits transit. Since calcium replacement enables to restore small intestinal transit, it is apparent that calcium rather than calcitonin is essential for normal small intestinal transit.

Animals↗

Disturbed gastric and small bowel transit in severe idiopathic constipation.

Many patients with severe idiopathic constipation complain of upper gastrointestinal symptoms, and these often persist after subtotal colectomy. To determine if there is a disturbance of upper gastrointestinal motility in this condition, we have studied gastric emptying for solids (111In-containing pancake) and liquids (99mTc-containing orange juice) for a longer period after a meal (6 hr) than in previously reported gastric emptying studies. Small bowel transit for solids was also measured. All patients had emptied their colon the day before the study. Twelve women (mean age 36 years) with a bowel frequency of less than once per week, proven slow intestinal transit, and a normal diameter colon were studied. Twelve healthy controls (eight female and four male, mean age 33) were also studied. As a group the constipated patients demonstrated no statistically significant delay in emptying during the first 3 hr, although the emptying rate for three of 12 individuals fell outside the normal range. However, at 6 hr after ingestion of the meal, six of 10 patients had residual gastric contents greater than normal--up to 48% solid residue (median: 11% for patients and 0% for controls, P < 0.01) and 40% of liquid (median 9% vs 0%, P < 0.01). Three of four patients with upper gastrointestinal symptoms 6 hr after the meal had gastric retention of solids markedly outside the normal range (48%, 32%, and 16%; normal < 4%). Small bowel transit time was assessed as the time for the solid phase to pass from the duodenum to the cecum; the constipated patients demonstrated delayed transit (median: 75 vs 55 min, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Targeting the abnormalities of gastroduodenal functions in functional dyspepsia.

The current definition of functional dyspepsia changes the previous concept of absence of organic disease to the presence of a functional alteration of the upper gastrointestinal tract. From a theoretical point of view, the alteration of any major gastrointestinal function may induce dyspeptic symptoms. However, both asymptomatic subjects with some gastrointestinal functional alteration and dyspeptic patients without a demonstrable dysfunction are not unusual. This may be explained at least in part by the more recent concept of visceral sensitivity. The potential role of acid secretion in the pathogenesis of functional dyspepsia as well as the positive effect of antisecretory drugs in a proportion of patients may be based on an increased gastric acid secretion and duodenal acid overload, a hypersensitivity to acid and/or the development of acid-mediated gastrointestinal motor abnormalities. Helicobacter pylori infection may play a role in this context. Both interdigestive and postprandial gastrointestinal motility, mainly a delayed gastric emptying and an altered intragastric distribution of nutrients, have been described to be disturbed in up to half of the patients with functional dyspepsia. This may also be an explanation for the high frequency of intestinal bacterial overgrowth in these patients. Most probably, visceral hypersensitivity should be present for motor alterations to induce symptoms. This is the basis for future development of new drugs in the management of this functional syndrome. The role of H. pylori in the pathogenesis of functional dyspepsia is a matter of discussion, but a proportion of patients benefit from eradication therapy and, therefore this therapeutic approach should be taken into account.

Duodenum↗