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PubMed1994

Synthesis of 2-imidazolidinylidene propanedinitrile derivatives as stimulators of gastrointestinal motility--II.

In a previous paper, we reported that a novel ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. In order to obtain more potent gastrointestinal motility enhancing agents than compound 2 and to examine the effects of various substituents both at a nitrogen atom (B) in the 2-imidazolidinylidene propanedinitrile moiety and a basic nitrogen atom (C), compounds 5-29 were synthesized and evaluated for acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically stimulated contractions of guinea pig ileum. Introduction of alkyl, benzyl, aryl or acyl groups to the nitrogen (B) or (C), remarkably influenced both activities. Among these, compounds 14 and 15 showed more potent AChE inhibitory activity (IC50 = 6.7, 6.8 nM, respectively) than compound 2 and were active in potentiating action on the ileal contraction (EC30 = 9.5, 11 nM, respectively) together with a negligible histamine H2-receptor blocking property. Furthermore, these compounds were found to be more effective in the enhancement of gastrointestinal motility in anesthetized rabbits than compound 2.

Animals↗

PubMed1977

[Significance of in-vitro studies ofr the evaluation of gastrointestinal motility].

To study the function of the smooth muscles taken from the gastrointestinal tract the simple organ bath or various superfusion techniques can be used. With the aid of these methods it is possible to measure contractile and electrical phenomena of the isolated muscles. In addition the reactivity to various stimuli can be tested. Such in-vitro-systems elucidate principal questions of physiology, pathophysiology, and pharmacology. However, there is no direct clinical significance of in-vitro-investigations of gastrointestinal motility up til now. The clinical benefit of such investigations can be seen in the better understanding of the pathophysiology and in the discovery of new drugs in the field of gastrointestinal motility.

Digestive System Physiological Phenomena↗

PubMed1988

Idiopathic cyclic nausea and vomiting--a disorder of gastrointestinal motility?

Eight patients (five men and three women) with previously unexplained recurrent cyclic episodes of nausea and vomiting are described. In these patients, the symptoms developed a mean of once every 3.2 months and persisted a mean of 3.5 days. None of the patients had an identifiable cause of their symptoms on conventional diagnostic tests. A detailed investigation of the gastrointestinal motility during an asymptomatic period revealed abnormal findings in all eight patients. Gastric hypomotility was substantiated in five patients, small bowel dysmotility in six, delayed gastric emptying in two, and gastric dysrhythmia in two. The data demonstrate that abnormal gastrointestinal motility occurs during an asymptomatic state in patients with cyclic episodes of nausea and vomiting. Because all patients with this syndrome had abnormal gastrointestinal motility but normal results of other gastrointestinal studies, idiopathic cyclic nausea and vomiting may be related to altered gastrointestinal motility.

Adult↗

PubMed1997

Gastrointestinal motility disorders in patients with inactive Crohn's disease.

BACKGROUND: Although some symptoms of Crohn's disease may be related to gastrointestinal motility disorders, studies on gastrointestinal motility in inactive Crohn's disease are lacking. METHODS: Fasting and postprandial motor activity (1 h) was recorded in the gastric antrum and upper small intestine of 35 patients with inactive Crohn's disease and 18 controls, using conventional manometry. RESULTS: Motor disorders were observed in 26 of 35 patients. The number of phase-II contractions was reduced (1.3 +/- 0.7/min versus 1.8 +/- 0.6/min in controls; P < 0.02) (mean +/- standard deviation), whereas the incidence of propagated single (2.2 +/- 3.2/h versus 0.5 +/- 0.6/h; P < 0.03) and clustered contractions (3.8 +/- 7/h versus 1.1 +/- 1.4, P < 0.04) was markedly increased. Motor abnormalities were more frequent and severe in patients with Crohn's ileitis than in controls, and in patients with gastrointestinal symptoms than in asymptomatic patients. CONCLUSION: Most patients with inactive, uncomplicated Crohn's disease show marked gastrointestinal motor disorders, characterized either by reduced incidence of small-bowel contractions and increased incidence of single or clustered propagated contractions.

Adolescent↗

PubMed1997

Effect of 5-hydroxytryptamine on gastrointestinal motility in conscious guinea-pigs.

Many studies have suggested that 5-hydroxytryptamine (5HT, serotonin) plays an important role in the control of gastrointestinal motility. However, most of these studies have been carried out on guinea-pig ileum in vitro. Therefore, we investigated the mechanisms of action of 5HT on gastrointestinal motility in conscious guinea-pigs. In order to investigate the effects of 5HT on gastrointestinal motility, extraluminal force transducers were sutured onto the serosal surfaces of the gastric antrum, duodenum and ileum and 5HT was infused intravenously. One of three types of 5HT antagonist or atropine was given before a 5HT infusion of 3.0 micrograms kg-1 min-1 was started. Regular cyclic patterns were observed from the gastric antrum to the ileum in both the fasted and fed states. 5HT increased the contraction amplitudes at all sites. 5HT-induced contractions in the gastric antrum and duodenum were significantly inhibited by methysergide, ondansetron and atropine, but not by ketanserin. In the ileum, only atropine inhibited 5HT-induced contractions. These results suggest that 5HT increases the gastrointestinal contraction amplitude mainly via a cholinergic pathway. 5HT3 receptors and 5HT1-like and/or 5HT2C receptors appear to be responsible for 5HT-induced gastric antral and duodenal contractions, but 5HT receptors other than 5HT1-like, 5HT2A, 5HT2C and 5HT3 receptors induce ileal contractions.

Animals↗

PubMed2006

Use of novel prokinetic agents to facilitate return of gastrointestinal motility in adult critically ill patients.

PURPOSE OF REVIEW: Intolerance of enteral feeding due to impaired gastrointestinal motility is common in critically ill patients. Strategies to prevent or treat gastrointestinal hypomotility include the use of prokinetic agents. Many currently employed prokinetic agents are associated with serious adverse drug reactions. The novel prokinetic agents - alvimopan, tegaserod, and dexloxiglumide - are reviewed. RECENT FINDINGS: Alvimopan exerts mixed, but generally favorable, effects on restoration of gastrointestinal motility in patients with postoperative ileus. The observation of increased opioid requirements (without increased pain scores) and associated clinical ramifications requires further study. Tegaserod stimulates the peristaltic reflex and improves motility in multiple sites along the gastrointestinal tract. Its efficacy in improving gastrointestinal hypomotility in the critically ill population has not yet been determined. Furthermore, its use has been associated with the development of ischemic colitis and increased requirement for abdominal/pelvic surgery. Dexloxiglumide may be beneficial for improving gastric emptying in critically ill patients, especially those receiving lipid-enriched enteral feeds. SUMMARY: Novel prokinetic agents show promise for management of gastrointestinal hypomotility in the critically ill population. However, further study is required before these agents can be recommended for use.

Adult↗

PubMed1993

[Effects of various histamine H2-receptor antagonists on gastrointestinal motility and gastric emptying].

Effects of various histamine H2-receptor antagonists (H2-RA) on gastrointestinal motility and gastric emptying were investigated. Ranitidine, nizatidine and cimetidine dose dependently induced contractions over the entire gastrointestinal tract, and the order of their effects was ranitidine > nizatidine > cimetidine. Roxatidine or famotidine had no effects on motility of the gastrointestinal tract. Ranitidine and nizatidine also induced contractions during the postprandial period and facilitated gastric emptying, while cimetidine, roxatidine or famotidine did not influence gastric emptying. Since acid reduction is thought to be the most important element of the treatment of peptic ulcer and reflux esophagitis, it was inferred that administration of a H2-RA selected with consideration of its property of facilitating gastrointestinal motility is effective in the treatment of patients with abnormal gastrointestinal motility.

Animals↗

PubMed1999

[Recovery of gastrointestinal motility following laparoscopic versus open cholecystectomy].

OBJECTIVE: To investigate the recovery of gastrointestinal motility after laparoscopic cholecystectomy (LC) and open cholecystectomy (OC). METHODS: Motilin (MOT), gastrin (GAS), electrogastrogram (EGG), the peristaltic sound recovery timing (PSRT) and the anorectum exhaust timing (AET) were determined in 30 patients having LC and 18 patients having OC. RESULTS: MOT, GAS, EGG frequency and EGG amplitude on the first, second and third day after operation in LC group were not significantly different in comparison with preoperative data (P > 0.05), but significant difference on the first and second postoperative day compared with preoperative data and data of the the LC group (P < 0.05). The PSRT and AET in the LC group were much shorter in comparison with the OC group (P < 0.05). CONCLUSIONS: The recovery of gastrointestinal motility after LC is earlier than OC, which justifies early feeding for patients after LC.

Cholecystectomy↗

PubMed2003

Effect of preinjury large bowel emptying on the inhibition of upper gastrointestinal motility after spinal cord injury in rats.

Spinal cord transection (SCT) inhibits gastrointestinal motility in rats. We evaluated the effect of preinjury large bowel emptying on this phenomenon. Male Wistar rats (N = 52) were fasted for 24 or 48 hr with water ad libitum and pretreated with lactose (0.8 g) or saline. Next, laminectomy followed or not by complete SCT between T4 and T5 vertebrae was performed. Phenol red recovery in the stomach and proximal, medial, and distal small intestine was determined 1 day later. In animals submitted to 24 hr fasting + saline, SCT increased gastric recovery by 42.8% and decreased medial small intestine recovery by 56.2%, while 48 hr fasting + saline or 24 hr fasting + lactose prevented the inhibition of gastric emptying (GE) in SCT animals. The 48 hr fasting + lactose prevented the inhibition of both GE and gastrointestinal transit. SCT-induced inhibition of upper gastrointestinal motility may involve enhancement of inhibitory reflexes, which can be prevented by large bowel emptying.

Animals↗

PubMed1996

Recovery of gastrointestinal motility following open versus laparoscopic colon resection in dogs.

The recovery of gastrointestinal motility was compared in dogs undergoing either laparoscopic or open sigmoidectomy. During surgery, bipolar recording electrodes were placed on the proximal and distal antrum, mid- and distal colon, and the rectum. Fasting myoelectric data were recorded postoperatively. Scintigraphic gastric emptying studies employing a solid test meal were performed before and after [postoperative day (POD) 2] operation. Ten radiopaque markers were given just before operation and retained markers were counted daily by abdominal x-ray. Gastric emptying on POD 2 was significantly delayed in the open group at 120 min compared with preoperative studies for the open group and compared with the laparoscopic group on POD 2 (P < 0.05 and P < 0.01, respectively). A significant difference in the number of retained markers was observed between the groups on POD 4 (P < 0.05). There were no significant differences in slow-wave frequency, presence of dysrhythmias in the proximal and distal antrum, or presence of either discrete or continuous electrical response activity in the colon and rectum between groups on any days. We conclude that using a laparoscopic approach results in more rapid recovery of fed-state gastrointestinal motility following colon resection. These data also suggest that myoelectric activity alone is not a sensitive enough parameter to detect these differences in recovery in this animal model.

Animals↗

PubMed1983

Footshock produces analgesia but no gastrointestinal motility effects in the rat.

The effect of inescapable footshock was determined on gastrointestinal motility in unanesthetized rats. Inescapable footshock did not affect gastric emptying, small or large intestinal transit. Footshock produced a brief, naloxone-reversible thermal analgesia. These data indicate that gastrointestinal motility and analgesia are controlled by different central nervous system opioid mechanisms.

Analgesia↗

PubMed1999

Gastrointestinal motility in patients with irritable bowel syndrome studied by using radiopaque markers.

BACKGROUND: Irritable bowel syndrome (IBS) has been identified as a physiologic abnormality, but no test has been established as a diagnostic standard for gastrointestinal dyskinesia in IBS patients. The aim of this study was to investigate gastrointestinal motility in patients with IBS by using radiopaque markers. METHODS: Gastrointestinal motility was studied in IBS patients (n = 72), constipation patients (n = 19), diarrhoea patients (n = 9), and healthy controls (n = 23). Using three types of radiopaque markers, analysis was performed to establish the transit time and a new indicator, the 'scattering index'. RESULTS: Transit times were not characteristic in IBS. The patients with IBS had significantly higher scattering indexes in the colon and total gut than the healthy controls and the patients with constipation and diarrhoea. The transit time and scattering index of the colon were linearly correlated in the healthy controls and the constipation and diarrhoea patients but were not correlated in the IBS patients. Using transit time and scattering index was a reliable means of evaluating gastrointestinal motility in IBS patients, with a sensitivity of 65% and a specificity of 96%. CONCLUSION: Three days' use of the radiopaque marker method was useful for providing an objective means of detecting gastrointestinal dysmotility in IBS patients.

Adolescent↗

PubMed2005

Influence of ghrelin on interdigestive gastrointestinal motility in humans.

BACKGROUND: Recent studies in animals have shown that ghrelin stimulates upper gastrointestinal motility through the vagus and enteric nervous system. The aim of the present study therefore was to simultaneously investigate the effect of administration of ghrelin on upper gastrointestinal motility and to elucidate its mode of action by measuring plasma levels of gastrointestinal hormones in humans. MATERIALS AND METHODS: Nine healthy volunteers (four males; aged 22-35 years) underwent combined antroduodenal manometry and proximal stomach barostat study on two separate occasions at least one week apart. Twenty minutes after the occurrence of phase III of the migrating motor complex (MMC), saline or ghrelin 40 mug was administered intravenously over 30 minutes in a double blind, randomised, crossover fashion. Ghrelin, motilin, pancreatic polypeptide, glucagon, and somatostatin were measured by radioimmunoassay in blood samples obtained at 15-30 minute intervals. The influence of ghrelin or saline on MMC phases, hormone levels, and intraballoon volume was compared using paired t test, ANOVA, and chi(2) testing. RESULTS: Spontaneous phase III occurred in all subjects, with a gastric origin in four. Administration of ghrelin induced a premature phase III (12 (3) minutes, p<0.001; gastric origin in nine, p<0.05), compared with saline (95 (13) minutes, gastric origin in two). Intraballoon volumes before infusion were similar (135 (13) v 119 (13) ml; NS) but ghrelin induced a longlasting decrease in intraballoon volume (184 (31) v 126 (21) ml in the first 60 minutes; p<0.05). Administration of ghrelin increased plasma levels of pancreatic polypeptide and ghrelin but motilin, somatostatin, and glucagon levels were not altered. CONCLUSIONS: In humans, administration of ghrelin induces a premature gastric phase III of the MMC, which is not mediated through release of motilin. This is accompanied by prolonged increased tone of the proximal stomach.

Adult↗

PubMed2000

Peptidergic regulation of gastrointestinal motility in rodents.

Peptides involved in the endocrine and enteric nervous systems as well as in the central nervous system exert concerted action on gastrointestinal motility. Mechanical and chemical stimuli which induce peptide release from the epithelial endocrine cells are the earliest step in the initiation of peristaltic activities. Gut peptides exert hormonal effects, but peptide-containing stimulatory (Ach/substance P/tachykinin) and inhibitory (VIP/PACAP/NO) neurons are also involved in the induction of ascending contraction and descending relaxation, respectively. The dorsal vagal complex (DVC), located in the medulla of the brainstem, constitutes the basic neural circuitry of vago-vagal reflex control of gastrointestinal motility. Several gut peptides act on the DVC to modify vagal cholinergic reflexes directly (PYY and PP) or indirectly via afferent fibers in the periphery (CCK and GLP-1). The DVC is also a primary site of action of many neuropeptides (such as TRH and NPY) in mediating gastrointestinal motor activities. The identification over the last few years of a number of neuropeptide systems has greatly changed the field of feeding and body weight regulation. By exploring the brain and gut systems that employ recently identified peptidergic molecules, it will be possible to elaborate on the central and peripheral pathways involved in the regulation of gastrointestinal motility.

Amines↗

PubMed1995

Synthesis of 2-imidazolidinylidene propanedinitrile derivatives as stimulators of gastrointestinal motility--III.

Recently, we reported that a ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. We have also found that introduction of substituents such as benzyl or 4-fluorobenzyl (i.e., giving 3 or 4) at the N-3 position of the moiety (A) significantly increased this activity. In this study, novel 2-imidazolidinylidene propanedinitrile derivatives possessing a thioether 5-15 were prepared and evaluated for in vitro assays; acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically induced contractions of guinea pig ileum. Compound 5, in which a nitrogen atom of compound 2 was replaced by a sulfur atom, was more potent than 2 in these tests. Also, in a series of thioether derivatives, introduction of substituents at the N-3 position of the 2-imidazolidinylidene propanedinitrile moiety markedly influenced both activities. In particular, compounds 12 and 13, which showed an excellent potency during in vitro study (AChE IC50 = 3.6 and 2.7 nM; ES. EC30 = 2.1 and 2.5 nM, respectively), were found to be more active in the enhancement of gastrointestinal motility in anesthetized rabbits than their corresponding parent compounds 3 and 4, respectively. In addition, compounds 12 and 13 showed lower affinity for the histamine H2-receptor than ranitidine. Therefore, these compounds may be potent and selective stimulators of gastrointestinal motility.

Acetylcholinesterase↗

PubMed1991

Effect of iron succinyl-protein complexes on gastrointestinal motility in the fasting dog.

Studying the gastrointestinal motor effects of iron compounds may help to elucidate the mechanism originating the gastrointestinal side effects of frequently reported during martial therapy. The aims of the present study were: (1) to examine the gastrointestinal motor effects of ferrous sulfate (reference compound) and (2) to compare its effects with those of two iron succinyl-protein complexes (ITF 1096 and ITF 282, an iron-albumin and iron-casein complex, respectively). In 6 fasting, conscious dogs, fitted with 8 bipolar electrodes and 3 strain-gauge force transducers along the gastrointestinal tract, gastrointestinal motor activity was recorded. Ferrous sulfate and iron succinyl-protein complexes were administered by an orogastric tube at two dose levels: the lower and higher dose levels were approximately equivalent to 10 and 30 mg/kg as Fe, respectively. In control experiments, 154 mM NaCl, ITF 211 (succinylated albumin) and ITF 297 (succinylated casein) were used. Administration of 154 mM NaCl did not affect gastrointestinal motility nor did it disrupt migrating motor complex (MMC) cycling. ITF 1096 and ITF 282, only at the higher dose, lengthened the MMC period and increased intestinal, but not gastric spike activity. The effects of ITF 211 and ITF 297 were similar to those of ITF 1096 and ITF 282. Ferrous sulfate, at the lower dose, lengthened the MMC period; the higher dose disrupted MMC cycling and induced intense, irregular spike bursts in the stomach and in the small bowel, accompanied, in 3 out of 6 dogs, by a prolonged tonic contraction of the upper small bowel. Four out of 6 dogs vomited after the higher dose of ferrous sulfate. No vomiting was observed with any of the other treatments. We conclude that ITF 1096 and ITF 282 have a markedly better gastrointestinal tolerability than ferrous sulfate.

Animals↗

PubMed2006

Evaluation of gastrointestinal motility by computerized analysis of abdominal auscultation findings.

BACKGROUND AND AIMS: To evaluate gastrointestinal motility by abdominal auscultation. METHODS: Abdominal auscultated sounds of 20 healthy adults and 10 diabetes mellitus patients with delayed gastric emptying were digitally recorded and then analyzed by computer while simultaneously monitoring the motility of the antrum of the stomach by ultrasonography. The auscultated sound, when the stomach wall was moving, was regarded as the gastroduodenal (GD) sound and when not moving as the intestinal (I) sound. The sound index (SI; the sum of the amplitude) was calculated to indicate the power of sound. Sounds were recorded for 15 min under fasting conditions and 60 min after a liquid meal. In six healthy adults, the gastroduodenal pressure was recorded under abdominal auscultation to detect any correlation between the motility index (MI; the sum of the area under the curve) and SI. RESULTS: A definite increase in the SI of the GD sound was observed after the liquid meal in comparison with that of the I sound. A positive correlation (r = 0.678) was observed between the SI of the GD sound and MI, thus, it was considered that the GD sound reflected the motility of the gastroduodenal wall. In the diabetes mellitus patients, the SI of the GD sound was significantly lower after food intake than in healthy adults. CONCLUSION: The results of the present study indicate that the abdominal auscultation test could be used as a new diagnostic method to detect any abnormality in gastrointestinal motility.

Adult↗

PubMed2000

Effect of altered gastric emptying and gastrointestinal motility on metformin absorption.

AIMS: The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects. METHODS: An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99mTc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic findings. RESULTS: Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,infinity) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma profile always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival. CONCLUSIONS: Metformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These findings have significant implications in the design of a metformin modified release dosage form.

Adult↗