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PubMed1984

Prostacyclin inhibits gastric emptying and small-intestinal transit in rats and dogs.

Prostacyclin (PGI2) antagonizes 16,16-dimethyl prostaglandin E2-induced diarrhea in rats, presumably by inhibiting the fluid accumulation of "enteropooling" in the small intestine. The effect of PGI2 on gastric emptying, small intestinal transit, and colonic transit was examined in rats and dogs to determine if interference with propulsion might also contribute to the antidiarrheal properties of this compound. Rats implanted with chronic duodenal cannulas were given subcutaneous PGI2 (0.1-1000 microgram/kg) followed 10 min later by intragastric 51Cr and a visually detectable duodenal transit marker. Forty-five minutes later, the animals were killed. Small-intestinal transit was expressed as the percentage of small intestinal length traveled by the visually detected marker. Gastric emptying was expressed as the percentage of the total 51Cr found in the small intestine. Subcutaneous PGI2 inhibited gastric emptying maximally at 10 micrograms/kg. Small-intestinal transit was significantly decreased at 50 micrograms/kg and almost completely suppressed at 1.0 mg/kg. Subcutaneous naloxone (0.5 mg/kg) given 10 min before and 20 min after subcutaneous PGI2 administration did not block PGI2's effects. Intravenous or oral PGI2 in doses as high as 0.2 or 10 mg/kg, respectively, had none of these effects. However, a high-dose intravenous bolus (1.0 mg/kg) or infusion (1.0 mg/kg X 45 min) both inhibited gastric emptying. Small intestinal transit was only decreased by PGI2 infusion, suggesting that this parameter was more sensitive to a sustained blood level than gastric emptying. Hourly injections of subcutaneous PGI2 (0.5 mg/kg) had no effect on rat colonic transit measured over a 3-h period after deposition of the transit marker through a colonic cannula in a manner similar to that described for small-intestinal transit above. Small-intestinal transit was also measured in dogs given a barium suspension through a chronic duodenal cannula. The animals simultaneously received subcutaneous PGI2 (10 micrograms/kg) and were given an additional treatment and an abdominal x-ray every 30 min thereafter. In vehicle-treated dogs, barium reached the cecal area in an average of 2.8 h after instillation. In PGI2-treated dogs, barium never reached the cecum in the 5-h examination period. Thus, PGI2 inhibits gastric emptying in rat and small-intestinal transit in rat and dog but has no effect on rat colonic transit. These properties could contribute to PGI2's antidiarrheal activity.

Animals↗
PubMed1984

[Motility inhibitors and secretion inhibitors].

Antidiarrheal substances interfering with either intestinal motility or intestinal secretion have been used for the management of acute diarrhea. Opiates are the motility inhibitors that appear particularly useful and among these drugs loperamide is the drug of choice due to its low risk of side effects. The question whether antisecretory effects of opiates observed in certain animal experiments is contributory to their antidiarrheal activity in man has not yet been definitely settled. With the exception of chlorpromazine that was felt to be especially useful in cholera, no other antisecretory drug has been used successfully against acute diarrhea. However, future development of new compounds may lead to drugs with potent anti-secretory activity but without unwanted extraintestinal side-effects.

Chlorpromazine↗
PubMed1997

Inhibition of pancreaticobiliary secretion by loperamide in humans.

Loperamide, a peripherally acting opiate receptor agonist with antidiarrheal action, inhibits ileal and colonic motor function. It was determined whether loperamide also affects gallbladder emptying and pancreatic enzyme secretion in humans. Plasma cholecystokinin (radioimmunoassay), gallbladder volume (ultrasonography), and intraduodenal bilirubin and amylase output (spot sampling) were measured at regular intervals before and during intraduodenal perfusion of an amino acid meal in 8 healthy subjects: once without and once with pretreatment of 8 mg loperamide, ingested 13 and 4 hours before the start of the meal. Loperamide decreased basal amylase output from 3.2 +/- 0.5 to 1.0 +/- 0.5 kU/h (P < .005) and abolished basal bilirubin output (21 +/- 5 vs. 0 +/- 0 micromol/h; P < .005) into the duodenum. Loperamide increased basal gallbladder volume from 28 +/- 4 to 39 +/- 4 mL (P < .0001) but was without effect on basal plasma cholecystokinin (2.7 +/- 0.3 vs. 3.0 +/- 0.3 pmol/L). During the amino acid meal, pretreatment with loperamide inhibited amylase output from 5.1 +/- 0.8 to 1.6 +/- 0.4 kU/h (P < .001), bilirubin output from 39 +/- 6 to 18 +/- 6 micromol/h (P < .0005) and gallbladder contraction from 47% +/- 3% to 26% +/- 6% (P < .05), whereas loperamide enhanced amino acid-stimulated plasma cholecystokinin from 4.5 +/- 1.6 to 7.6 +/- 1.0 pmol/L (P < .05). It is concluded that loperamide inhibits basal and amino acid-stimulated gallbladder motility and intraduodenal output of bilirubin and amylase, despite an enhanced postprandial cholecystokinin release.

Adult↗
PubMed1987

The acute effects of the enkephalin analogue BW 942C in humans.

BW 942C hydrochloride is an enkephalin analogue that has exhibited a wide separation between antidiarrheal dosages and dosages inducing adverse effects in animals. This has likewise been the case in humans when administered orally. In this study, the safety and tolerance of single 0.5-mg doses of intravenous BW 942C compared with placebo were assessed in humans. Four healthy male volunteers received BW 942C, and two received placebo. The effects of BW 942C on serum growth hormone (GH), luteinizing hormone (LH), prolactin (PR), and follicle-stimulating hormone (FSH) were assessed in three of these volunteers. No significant changes were apparent in vital signs, in clinical chemistry, hematologic and urine studies following BW 942C administration. BW 942C did not appear to alter mood as assessed by two psychologic mood scales. Prolactin levels tended to increase in volunteers receiving BW 942C two hours postinfusion. Luteinizing hormone concentrations decreased slightly at two and six hours. No trends in FSH or GH could be identified. Pulmonary function testing did not reveal any significant changes in oximetry, spirometry, or plethysmography in any of the subjects. A marked decrease in CO2 responsiveness in two subjects may indicate that BW 942C has mild ventilatory depressant effects. Untoward effects experienced in volunteers receiving BW 942C included heaviness in the limbs, nasal stuffiness, mouth dryness, facial flushing, skin rash, and prickling sensations. These effects bear a striking similarity to those experienced after parenteral administration of other enkephalin analogues. Intravenous administration of BW 942C up to 0.5 mg appears safe from a laboratory, physiologic, and clinical perspective with unusual untoward effects that may preclude rational use of the drug by the parenteral route.

Adult↗
PubMed1987

Limitations of indirect methods of estimating small bowel transit in man.

Experiments were carried out in healthy volunteers to explore the utility of a new [14C]lactulose breath test for measuring small intestinal transit time in man and to use this procedure to test whether two antidiarrheal agents, codeine and clonidine, alter small intestinal transit time during digestion of a liquid meal. In an initial validation study performed in 12 subjects (three studies in each subject), a liquid test meal containing 10 g [14C]lactulose was administered and the colonic entry time estimated from the time course of 14CO2 excretion in breath compared with that of H2 excretion. There was a fair correlation (r = 0.77; P less than 0.001) between results obtained by the two methods; both methods gave similar results, but 14CO2 output was delayed when compared to H2 output and was incomplete. The meal also contained xylose and [13C]glycine, permitting the duodenal entry time of the meal to be estimated by the appearance of xylose in blood and 13CO2 in breath, respectively. The same liquid meal was then used to examine the effect on small intestinal transit time (colonic entry time minus duodenal entry time) of codeine or clonidine. 99Tc-sulphur colloid was also added to the meal to permit a comparison of small intestinal transit estimated by imaging with that estimated by the 14CO2-lactulose breath test. 99Tc radioactivity appeared in the cecum (as assessed using gamma scintigraphy) about 2 hr before 14CO2 radioactivity appeared in breath; the correlation between transit time estimated by the two methods was moderate (r = 0.61; P less than 0.05). Based on the [14C]lactulose data, small intestinal transit time ranged from less than 1 to 3 hr for a liquid meal containing 10 g lactulose; within-subject variation (coefficient of variation 17%) was considerably less than between-subject variation (coefficient of variation 56%). Codeine increased the small intestinal transit time significantly (from 2.7 +/- 0.3 hr to 5.0 +/- 0.9 hr; mean +/- SE), whereas clonidine did not alter small intestinal transit time, as estimated by the colonic entry time minus duodenal entry time. Neither drug influenced duodenal entry time. These results suggest that the [14C]lactulose breath test, which has only moderate accuracy, may have occasional utility as a convenient, noninvasive method for estimating small intestinal transit time in man. However, this study also suggests that indirect methods of estimating small bowel transit in man have limitations, variability, and possibly may lack the desired sensitivity.

Antidiarrheals↗
PubMed1993

Quality of life after restorative proctocolectomy with a pelvic ileal reservoir compares favorably with that of patients with medically treated colitis.

There remains some reluctance among physicians to refer patients for restorative proctocolectomy (RP). They argue that their patients would be worse off with a pouch because of the attendant problems of urgency and frequent bowel actions. The aim of this study was to compare quality of life in patients who had undergone RP with that of patients with ulcerative colitis on long-term medical treatment. A detailed questionnaire and the Hospital Anxiety and Depression (HAD) test were completed by 103 patients who had undergone RP and by 95 patients with ulcerative colitis on medical treatment and in remission attending a gastroenterology clinic. Patients with a pouch had a greater frequency of bowel action [five times per 24 hours (range, 4-7) vs. two times per 24 hours (range, 1-3); P < 0.001] but less urgency of defecation [12/103 (11.7 percent) vs. 69/95 (72.6 percent); P < 0.001] than patients with medically treated colitis. Efficiency of evacuation, discrimination between flatus and feces, use of perianal pads, and perianal soreness were similar. Use of antidiarrheal medication was more common in the pouch group [53 of 103 patients (51.5 percent) vs. 3 of 95 patients (3.2 percent); P < 0.05], whereas use of topical steroids was more common in medically treated patients [40 of 95 patients (47.1 percent) vs. 9 of 103 patients (8.7 percent); P < 0.05]. Limitation of social activity and HAD scores were significantly higher in medically treated patients. Quality of life for patients with a pouch appears to be as good as that for patients with medically treated colitis.

Adolescent↗
PubMed1995

Biofeedback for the treatment of fecal incontinence. Long-term clinical results.

UNLABELLED: Biofeedback therapy has been proposed as a treatment for fecal incontinence with good, short-term results. PURPOSE: This study was designed to assess long-term clinical results of biofeedback therapy compared with medical therapy alone and to assess manometric results in patients treated with biofeedback. METHODS: Two groups of incontinent patients were studied. Group 1 consisted of 16 patients (3 males and 13 females; mean age, 59.9 years). Etiologies treated by biofeedback included descending perineum syndrome (7), postfistula or hemorroidectomy (4), and miscellaneous (5). Group 2 consisted of eight patients (two males, six females; mean age, 62.2 years). Etiologies treated with medical treatment alone (including enema and antidiarrheal therapy) included descending perineum syndrome (3), postfistula or hemorroidectomy (2), and miscellaneous (3). The incontinence score was initially 17.81 +/- 3.27 (standard deviation) in Group 1 and 17.0 +/- 2.77 in Group 2. Resting pressure of the upper and lower anal sphincter, maximum squeezing pressure, and duration of contraction were not initially different in Groups 1 and 2 but were significantly lower than in the control group of patients without incontinence (n = 12; 8 males, 4 females; mean age, 66.4 years) (P < 0.05). Follow-up duration was 30 months, with intermediate clinical score at 6 months for Group 1. RESULTS: After biofeedback therapy, the incontinence score at 30 months was lower in Group 1 (14.43 +/- 6.35 vs. 17.81 +/- 3.27; P < 0.035) and unchanged in Group 2 (18.0 +/- 2.72 vs. 17.0 +/- 2.77). However, in Group 1 the score at 6 months was much lower than at 30 months (6.31 +/- 7.81 vs. 14.43 +/- 6.35; P < 0.001). Only the amplitude of voluntary contraction and upper anal pressure (51.1 (range, 27-90) vs 36.7 (range, 20-80) mmHg) were significantly increased (81.5 (range, 55-120) vs. 62.1 (range, 30-90) mmHg; P < 0.05). CONCLUSION: Biofeedback improved continence at 6 months and at 30 months. However, the score at 6 months was much better, suggesting that the initial good results may deteriorate over a long time. These data suggest that it could be useful to reinitiate biofeedback therapy in some patients.

Adult↗
PubMed1986

Pathogenesis and pharmacology of diarrhea.

The etiological factors involved in diarrhea are multiple. Also the mechanisms and mediators involved are multiple: intracellular mediators (Ca, cAMP, cGMP, calmodulin, phospholipids), extracellular mediators (hormones, neurotransmitters, prostaglandins, enterotoxins...), intramural blood flow and oxygen, intestinal motility (local- and peristaltic motility). Till now, antidiarrheals are not so versatile that they provide a solution to all types of diarrhea. The mechanisms of action of fluid replacement therapy, loperamide, alpha 2 agonist and some nonsteroidal anti-inflammatory substances are reviewed.

Acetylcholine↗
PubMed1987

Effect of lidamidine on transepithelial potential difference evoked by prostaglandin E2 in human jejunum.

The effect of the infusion of lidamidine, an antidiarrheal drug, on the change in transepithelial potential difference (TPD) induced by the infusion of prostaglandin E2 (PGE2) was examined in perfused human jejunum in vivo. The increase in luminal negativity of TPD produced by 3 X 10(-7) M PGE2 was significantly decreased from 2.8 +/- 0.5 mV to 1.2 +/- 0.5 mV by the superimposed infusion of 2 X 10(-3) M lidamidine. This result may suggest that lidamidine has an inhibitory effect on intestinal Cl secretion which is stimulated by PGE2.

Action Potentials↗
PubMed2000

Loperamide: novel effects on capacitative calcium influx.

Loperamide is a widely used antidiarrheal that primarily acts at nanomolar concentrations through activation of opioid receptors in the gastrointestinal tract. At somewhat higher concentrations, loperamide blocks calmodulin activity, calcium channels, N-methyl-D-aspartate-receptor channels, and maitotoxin-elicited calcium influx. Loperamide at micromolar concentrations has now been shown to have a remarkable stimulatory effect on the capacitative calcium influx that is triggered in many cells by depletion of the inositol-trisphosphate-sensitive stores of calcium in the endoplasmic reticulum. The mechanism whereby loperamide enhances levels of intracellular calcium elevated by capacitative calcium influx is, as yet, undefined.

Adenosine Triphosphate↗
PubMed2001

Control of irinotecan-induced diarrhea by octreotide after loperamide failure.

Diarrhea is a well-recognized side effect of chemotherapy, which affects the quality of life and when refractory is potentially life threatening. Irinotecan (CPT-11) is associated with an elevated incidence of chemotherapy-induced diarrhea and subsequent morbidity. Standard antidiarrheal treatment is based on high-dose loperamide, but this agent is associated with a significant failure rate. Octreotide is active against chemotherapy-induced diarrhea caused by fluoropyrimidines and irinotecan, with a distinct mechanism of action. We administered octreotide in a phase I trial in 37 patients who received irinotecan and experienced loperamide-refractory diarrhea, 23 of whom experienced grade III-IV diarrhea and were treated with loperamide. The 13 patients in whom to loperamide failed to control diarrhea received octreotide, with a high response rate (92%). We conclude that octreotide is effective against loperamide-refractory diarrhea resulting from irinotecan-based chemotherapy.

Adult↗
PubMed1985

Prevention and treatment of infectious diarrhea. Speculations on the next 10 years.

The next decade should explode with exciting schemes and novel agents for the prevention and treatment of infectious diarrhea. The development of oral, nonabsorbed antibiotics will continue, but new antidiarrheal drugs, such as gastrointestinal hormone analogues and alpha-adrenergic agonists, will be added to our therapeutic armamentarium. Improved oral rehydration solutions, such as glycine in electrolyte solution, promise to revolutionize the management of diarrhea by diminishing diarrheal stool volume to the point where losses are too small to be clinically relevant. Infant formulas and adult oral solutions fortified with antibodies raised against selected enteropathogens may provide a way to prevent infectious diarrheas in infants and travelers. Advances in genetic engineering will usher in a new era of experimental and licensed enteric vaccines, including those against cholera, Escherichia coli, Shigella, typhoid fever, and rotavirus.

Animals↗
PubMed1990

Pathophysiology of acute diarrhea.

Diarrhea, a major health problem worldwide, is both a sign and a symptom. As a symptom, diarrhea has been described as an increase in stool frequency, an increase in stool volume, and/or a decrease in stool consistency. As a sign, diarrhea is characterized by an increase in stool water excretion to greater than 150 to 200 ml every 24 hours. Four mechanisms that may be responsible for the alterations in fluid and electrolyte movement associated with diarrhea are increased luminal osmolality, decreased fluid absorption, increased intestinal secretion, and altered intestinal motility. Specific pathogenic mechanisms for acute infectious diarrhea include tissue invasion, enterotoxin production, and adhesion of infectious agents to epithelial cells. Antidiarrheal agents remove secretagogues from the intestinal tract, stimulate fluid absorption, and inhibit electrolyte movement.

Acute Disease↗
PubMed1986

Further validation of in vivo and in vitro pharmacological procedures for assessing the alpha 2/alpha 1-selectivity of test compounds: (2). Alpha-adrenoceptor agonists.

Eighteen chemically dissimilar alpha-adrenoceptor agonists were assessed in 6 different tests. The antidiarrheal activity of the compounds was highly correlated with the diuretic activity. Both activities were highly correlated with the inhibition of [3H]clonidine or [3H]idazoxan binding; the degree of correlation with inhibition of [3H]WB4101 binding or with antiptotic activity was much less. Antiptotic activity was better correlated, although still poorly, with inhibition of [3H]WB4101 binding than with inhibition of [3H]clonidine or [3H]idazoxan binding. The in vivo antiptotic/diuretic or antiptotic/antidiarrheal potency ratios both reflected the known alpha 2/alpha 1-selectivity of the compounds tested and were significantly correlated with the in vitro potency ratios between inhibition of [3H]WB4101 binding on one hand and of [3H]clonidine or [3H]idazoxan binding on the other. The reliability of the above models for measuring alpha 1- and alpha 2-adrenoceptor agonistic activity and selectivity is discussed.

Adrenergic alpha-Agonists↗
PubMed1985

Effects of morphine and atropine on motility and transit in the human ileum.

We examined motility of the ileocecal region, pressures at the ileocecal sphincter, and ileal flow after therapeutic doses of morphine and atropine. Using a factorial design in two cells of 8 (2(3] subjects, drugs were given during fasting and postcibally. Morphine (100 micrograms/kg body wt as a bolus intravenously) and atropine (7 micrograms/kg body wt as a bolus) stimulated migrating bursts of phasic activity (similar to phase III of the migrating motor complex). Morphine initially stimulated ileal flow, but atropine could not be shown to have this effect. Atropine reduced markedly the occurrence of sporadic pressure waves in the ileum, but morphine did not. Whereas atropine delayed mouth-to-ileum transit of polyethylene glycol, given in a mixed meal, morphine did not. Naloxone, in the dosage used (40 micrograms/kg body wt as a bolus, followed by 10 micrograms/kg body wt X h) had no independent effects on motility or flow, but did blunt the stimulatory effects of morphine and atropine on migrating motor complexes. We could not demonstrate an effect of any drug on the transit of lactulose from terminal ileum to cecum. Neither morphine nor atropine had impressive effects on tone at the ileocecal sphincter. These observations, while not specifying the mechanisms for constipation after opiates or anticholinergics, highlight the complexities of small bowel transit in humans and point out that the antidiarrheal effects of drugs are probably multifactorial.

Adult↗
PubMed1986

Effect of lidamidine hydrochloride and loperamide on gastric emptying and transit of the small intestine. A double-blind study.

We performed a double-blind randomized study in 24 healthy volunteers, to evaluate the effects of two doses of lidamidine hydrochloride, loperamide, and placebo on transit of the small intestine and gastric emptying. Transit time of the small intestine was determined by measuring the rise in breath hydrogen excretion after ingestion of lactulose. Although there was a trend for prolonged intestinal transit time in both lidamidine groups, this difference was not significant compared with that in the placebo group. Loperamide significantly slowed transit when compared with placebo or lidamidine (p less than 0.001). Gastric emptying was assessed by using a solid-phase radiolabeled meal. Three parameters of gastric emptying were analyzed: half-emptying time, area under the gastric emptying curve, and beta. Although there was a trend for a longer half-emptying time in the group that received 12 mg of lidamidine, this difference approached, but did not reach, statistical significance (p = 0.06) compared with placebo. The area under the gastric emptying curve, a potentially more sensitive parameter for measuring gastric emptying, was significantly increased in the group receiving 12 and 18 mg of lidamidine (p less than 0.05) compared with the group receiving loperamide or placebo. In summary, lidamidine significantly delayed gastric emptying but had no significant effect on small bowel transit. These data suggest that the antidiarrheal properties of lidamidine are the result of enhanced absorption or inhibition of secretion of fluid and electrolytes.

Adolescent↗
PubMed1990

A double-blind, controlled trial of bioflorin (Streptococcus faecium SF68) in adults with acute diarrhea due to Vibrio cholerae and enterotoxigenic Escherichia coli.

The therapeutic efficacy of Bioflorin (Streptococcus faecium SF68; Gipharmex, Milan, Italy) in acute watery diarrhea was evaluated in 183 Bangladeshi adults. Vibrio cholerae organisms were isolated from stool cultures in 114 patients, and enterotoxigenic Escherichia coli organisms were isolated in 41. In addition to IV rehydration, patients were randomly assigned to receive either capsules of Bioflorin containing 1 X 10(9) of live SF68 or capsules of placebo containing killed SF68 once every 8 hours for 3 days. No other drugs were allowed during this period. Bioflorin was well tolerated. It is concluded that Bioflorin has no demonstrable antidiarrheal property in adults with acute diarrhea due to V. cholerae or enterotoxigenic E. coli infection.

Adult↗
PubMed1984

Alpha-2 receptors in the gastrointestinal system: a new therapeutic approach.

Alpha-2 receptor activation mediates the inhibition of a number of gastrointestinal functions including gastric and intestinal secretions. Alpha-2 receptors are located in the brain and presynaptically on cholinergic nerve terminals; activation of either inhibits vagus nerve activity. Intestinal secretions are inhibited by postsynaptic alpha-2 receptors located on intestinal epithelial cells. Agents which selectively activate alpha-2 receptors in the gut may therefore be beneficial in treating gastric ulcers and diarrheal states. Two such agents which activate alpha-2 receptors in the gut are WHR-1370A [1-n-butoxy-3-(2,6-dimethylphenylcarbamoyl) guanidine hydrochloride] and lidamidine. WHR-1370A is a potent gastric antisecretory and antiulcer agent which inhibits the release of acetylcholine from the vagus nerve. WHR-1370A's activity is blocked by yohimbine. Lidamidine is a clinically effective antidiarrheal agent. Lidamidine's response is partially inhibited by yohimbine in animal diarrheal models. Alpha-2 agonists represent a new class of drugs which have a promising future in the treatment of gastrointestinal disorders.

Adrenergic alpha-Agonists↗