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Prokinetic agents for lower gastrointestinal motility disorders.

Prokinetic agents are currently being investigated as potential therapies for motility disorders of the lower gastrointestinal tract. Cholinergic agonists such as bethanechol are known to improve postoperative ileus but are limited because of side effects. Dopamine antagonists such as domperidone appear to have maximal prokinetic effect in the proximal gastrointestinal tract and are effective for such conditions as gastroparesis and gastroesophageal reflux, but they appear to have little physiologic effect in the colon or in colonic motility disorders. Naloxone, an opioid antagonist, appears to hold promise in patients with irritable bowel syndrome, small intestinal pseudo-obstruction, and constipation. Erythromycin exerts its prokinetic effect by acting as a motilin agonist; it has been used in the treatment of diabetic gastroparesis and appears to improve symptoms of colonic pseudo-obstruction and postoperative ileus. Metoclopramide, a combined cholinergic agonist and dopamine antagonist, is currently used exclusively for proximal motility dysfunction. Cisapride appears to hold the most promise for patients with colonic motility disorders. In patients with postoperative ileus, cisapride is associated with an increased return of bowel function compared with placebo. In patients with chronic constipation, cisapride increases stool frequency and decreases laxative abuse in both adults and children. Hopefully, as an understanding of gastrointestinal motility increases, effective prokinetic agents will be developed that will improve symptoms of patients with large bowel motility disorders and may also help to predict those patients who benefit from surgical management for constipation.

Gastrointestinal Motility↗

Effects of the natural and unnatural isomers and degradation products of enprostil on gastric acid secretion and gastrointestinal motility in the rat.

The gastric antisecretory and gastrointestinal (GI) motility activity of the natural and unnatural allenic isomers and degradation products of enprostil (methyl(+/-)-7-[(1R*,2R*,3R*)-3-hydroxy-2-[(E)-(3R*)-3-hydroxy-4-phenoxy - 1-butenyl]-5-oxocyclopentyl]-4,5-heptadienoate, RS-84135-004) were studied in the rat. The natural R-allenic isomer of enprostil was the most potent antisecretory compound. The 8-iso-enprostil, enprostil free acid, and the 5-acetylene isomer had somewhat less activity while the other compounds were relatively inactive. The natural and unnatural allenic isomers increased intestinal dye transit with the same rank potency as the gastric antisecretory activity. Enprostil, 8-iso-enprostil, prostaglandin A-enprostil and enprostil free acid, all increased intestinal dye transit.

Animals↗

Inhibition of gastrointestinal motility by MPTP via adrenergic and dopaminergic mechanisms.

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was injected intraperitoneally in mice and caused an acute inhibition (of over 60%) of gastrointestinal motility, which was measured by the transit of charcoal. This inhibition was not related to conversion of MPTP to MPP+. Administration of the beta-adrenergic blocker propranolol significantly reduced, but did not completely block, the effect of MPTP. The dopaminergic blocker haloperidol also partly reversed the effects of MPTP. When these blockers were administered together, the action of MPTP was fully blocked. The results indicate that the toxin acted by releasing catecholamines (presumably norepinephrine and dopamine), thereby inhibiting motility.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Antagonism of endotoxin-induced disruption of equine gastrointestinal motility with the platelet-activating factor antagonist WEB 2086.

The effect of pre-treatment with a selective platelet-activating factor (PAF) antagonist, WEB 2086, on the actions of low-dose endotoxin was evaluated in ponies prepared with gastrointestinal strain gauges. Endotoxin (0.1 microgram/kg i.v.) produced a marked reduction in gastric contraction amplitude and rate, and an increased frequency and reduced duration of jejunal phase III activity fronts (AFs). WEB 2086 (6.6 mg/kg) administered i.v. 10 min before the endotoxin, produced significant antagonism (P less than 0.001) of the effect of endotoxin on gastric contraction amplitude and rate. The combination of WEB 2086 and endotoxin produced gastric contractions of significantly (P less than 0.01) higher frequency than in the control studies. WEB 2086 also reduced endotoxin-induced abnormal phase III AFs in the jejunum and increases in heart rate and packed cell volume. These results provide evidence that endogenous PAF plays a role in mediating the acute effects of endotoxin on equine gastrointestinal motility.

Animals↗

[Clinical and experimental studies on gastrointestinal motility following total colectomy: direct measurement (strain gauge force transducer method, barium method) and indirect measurement (hydrogen breath test, acetaminophen method)].

In a clinical study, we examined the clinical assessment of bowel function and lactulose hydrogen breath test in 14 patients after total colectomy. All patients within one year after ileostomy closure had 'poor' function and showed no increase of hydrogen breath gas concentration. 10 of 12 patients more than one year showed increase of hydrogen breath gas concentration, and 8 of them had 'fair' function. The oro-neorectal transit time (ONTT) in 'poor' group was shorter than in 'fair' group and control (p less than 0.05). The increase of hydrogen breath gas suggests changes of bacterial flora and colonization of the remained ileum. In an experimental study, we performed subtotal colectomy with the J-pouch reservoir in 11 dogs. We examined ONTT with barium method, gastric emptying with acetaminophen method, and gastrointestinal motility with strain gauge force transducers. Although ONTT at one month after operation had been shorter than control, ONTT at 3 and 6 months became longer than at one month. The gastric emptying after subtotal colectomy was significantly slower than control. Although the propagation velocity of interdigestive migrating complex (IMC) in the jejunum and ileum at 2 weeks had been faster than control, the velocity at 4 weeks and 3 months became slower than at 2 weeks. The frequency of IMC and prolonged propagated contraction in the J-pouch reservoir decreased. The specimen of J-pouch reservoir resected at 6 months showed villous atrophy, crypt elongation, decrease of muscle layers thickness and disappearance of solitary follicles. Therefore, the suppressed motility in each sites of the gastrointestinal tract, increase of anaerobic and colonization of the ileum implied 'adaptation' after total colectomy.

Acetaminophen↗

SC-49518 enhances gastric emptying of solid and liquid meals and stimulates gastrointestinal motility in dogs by a 5-hydroxytryptamine4 receptor mechanism.

SC-49518 (N-[exo-(hexahydro-1H-pyrrolizine-1-yl)methyl]-2-methoxy-4- amino-5-chlorobenzamide HCl), a new benzamide gastrointestinal prokinetic compound, was investigated to determine its ability to stimulate gastrointestinal motility in vivo and whether these actions could be mediated by agonist activity at the putative 5-hydroxytryptamine (5-HT)4 receptor. In conscious fasted dogs with strain gauge transducers and myoelectrodes, SC-49518 disrupted gastric and small intestinal migrating motility complex cycling for more than 3.5 hr. It stimulated gastric antral contractile and intestinal myoelectric spike burst activities during the normally quiescent Phase I of the migrating motility complex at doses as low as 0.01 and 0.03 mg/kg i.v., respectively. In a canine model of gastroparesis, SC-49518 reversed completely alpha-2 adrenergically delayed gastric emptying of a solid meal with an ED50 value of 0.1 mg/kg intragastrically and partially reversed delayed emptying of a liquid meal. SC-49518, like 5-HT, cisapride and renzapride, acted as an agonist (EC50 = 6.6 +/- 1.1 x 10(-8) M) at the putative 5-HT4 receptor in rat esophageal tunica muscularis mucosae by relaxing carbachol-induced contractions. SC-49518 was a partial agonist at 5-HT4 receptors, but also blocked high affinity (5-HT4-mediated) responses to 5-HT (10(-9) M to 3 x 10(-7) M) in guinea pig ileum with a pA2 value of 8.39.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Intraluminal lipids modulate avian gastrointestinal motility.

Infusion of lipids into the ileum delays gastric emptying and intestinal transit time in some species. The aim of this study was to characterize the actions of intraluminal lipid infusion on gastrointestinal electrical activity in chickens. Animals were prepared for electromyography with chronic electrodes in stomach, duodenum, and small intestine. Two catheters were chronically placed in the esophagus and ileum to infuse equimolar doses of either oleic acid (OA) or triolein (TO). Both OA and TO, esophageally infused, inhibited the frequency of the gastroduodenal cycle and increased the frequency of antiperistaltic spike bursts in the duodenum. Ileal infusion of OA, but not of TO, produced the same effects. Both esophageal and ileal OA infusion increased the duration of the migrating myoelectric complex (MMC) and decreased the speed of propagation of phase III. In conclusion, intraluminal infusion of lipids modulates gastrointestinal motility by decreasing the frequency of the gastric cycle, increasing duodenogastric refluxes, and elongating the MMC. These actions could delay gastric emptying and increase transit time, which suggests the presence of an "ileal brake" mechanism similar to that described in mammals.

Animals↗

Evidence for serotonergic system involvement in the effect of morphine on gastrointestinal motility in the rat.

1. Intestinal motility was measured by the transit of charcoal meal through the small intestine of the rat. 2. Morphine given subcutaneously induced a reduction in the gastrointestinal transit (GIT), and the response was dose-dependent (0.1-2.5 mg/kg). 3. The inhibitory effect of morphine was antagonized by prior subcutaneous administration of naloxone (1 mg/kg). 4. Depletion of serotonergic neurons by para-chlorophenylalanine (100 mg/kg, ip, 3 days) completely abolished the inhibitory action of morphine. 5. Methysergide (5 mg/kg, sc) and ketanserin (5 mg/kg, sc) also reduced the morphine effect. 6. Destruction of serotonergic neurones by intracerebroventricular injection of 5,7-dihydroxytryptamine (20 mu/kg) abolished the effect of morphine. 7. These observations provide some evidence for the involvement of a central serotonergic system in the effect of morphine on gastrointestinal motility.

5,7-Dihydroxytryptamine↗

Effects of oral clarithromycin and amoxycillin on interdigestive gastrointestinal motility of patients with functional dyspepsia and Helicobacter pylori gastritis.

BACKGROUND: Clarithromycin and amoxycillin are antibiotics commonly used in association for Helicobacter pylori eradication. Because this treatment, which lasts 1-2 weeks, is frequently associated with gastrointestinal symptoms, we investigated the effects of these antibiotics on gastrointestinal motility. PATIENTS AND METHODS: Gastroduodenal motility was recorded in 14 patients with functional dyspepsia and H. pylori gastritis by means of a low-compliance manometric system with four recording ports in the stomach and four in the duodenum. Two tablets of clarithromycin 250 mg (seven patients, clarithromycin group) or one of amoxycillin 1 g (seven patients, amoxycillin group), ground and dissolved in 20 mL of water, were given randomly and in double-blind manner 30 min after the end of the first activity front (AF) of the migrating motor complex (MMC) or, in the absence of AFs, after at least 200 min of recording. Recording continued until an AF was observed during the subsequent 200 min. RESULTS: Clarithromycin administration was followed by a typical gastroduodenal AF in a significantly higher number of patients than for amoxycillin administration. In addition, the time lag between clarithromycin administration and the appearance of AFs was 48 min +/- 8.5 (mean +/- s.d.), significantly shorter than after amoxycillin (121 min +/- 29). The clarithromycin-related duodenal AFs showed a duration of 6.6 min +/- 1.5, significantly longer than that of the spontaneous AFs (3.6 min +/- 1.2, P < 0.01), while the amoxycillin-related AFs were not significantly different from the spontaneous ones. CONCLUSION: Clarithromycin stimulated cyclic gastroduodenal motility, while amoxycillin was ineffective. It is likely that symptoms during the eradication treatment are due to this effect of clarithromycin.

Administration, Oral↗

Control of gastrointestinal motility by peptides: old peptides, new tricks--new peptides, old tricks.

The discovery of new peptides that may or may not be members of existing peptide families is stimulating research in the field of gastrointestinal motility. Before their function in control of human motility can be predicted, both anatomic and functional pathways must be determined in a number of animal models. In many instances this has just begun. In other instances old concepts must be revised. This review examines the recent findings that motor actions attributable to VIP and by extension to its colocalized family member PHI may occur by turning off a tonic release that has held the muscle in a relaxed state. For the opioid family, some of the very complex actions are probably attributable to its action to inhibit the tonic release of VIP. For the tachykinin/neurokinin family, the focus is on the potential role as a sensory transmitter released antidromically from afferent capsaicin-sensitive nerve endings. In summarizing the actions of galanin, the reader is cautioned against any extrapolation to other species, because the actions and structure of the peptides have been found to be different in each species examined. CGRP, again a sensory transmitter found colocalized with substance P, tends to exert an opposite action on the smooth muscle from substance P (that of relaxation), and the interactions between these peptides may well prove to be important in gastrointestinal reflexes. The PP, PYY, and NPY family require much more study in gastrointestinal motor systems but appear to act as presynaptic inhibitory transmitters in a variety of local motor reflexes. One caveat from one who studies these systems is never to predict the action of a new or old peptide in your system of study, because the complexity of the system appears to determine the action expressed.

Animals↗

Duodenogastric bile reflux and gastrointestinal motility in pathogenesis of functional dyspepsia. Role of cholecystectomy.

To establish the pathogenic role of duodenogastric reflux in dyspeptic symptoms we have compared the clinical features, gastrointestinal motility, and rates of duodenogastric bile reflux in 12 cholecistectomized dyspeptic patients, 12 dyspeptic patients with intact gallbladder, and 12 healthy controls. Specific symptoms were scored for severity and frequency. Gastrointestinal manometry was performed during 3 hr of fasting and 2 hr postprandially. Simultaneously, samples of duodenal and gastric contents were obtained sequentially for quantification of bile acids. Results show that symptom global severity (9.6 +/- 0.4 vs 8.8 +/- 0.7) and frequency (9.9 +/- 0.8 vs 9.0 +/- 0.5) were similar in both dyspeptic groups; only abdominal pain was milder in cholecystectomized patients (1.9 +/- 0.1 vs 2.6 +/- 0.2; P < 0.05). Fasting gastric bile acid concentrations were higher in cholecystectomized patients (P < 0.05) and antral postcibal motility lower (P < 0.05) than in the groups. No relation among gastric hypomotility, duodenogastric bile reflux, and symptom scores was detected. We concluded that patients with functional dyspepsia and a prior cholecystectomy have clinical features similar to those with gallbladders, but some physiological features are dissimilar: antral motility is decreased and duodenogastric bile reflux is increased. Thus, a uniform clinical expression of various pathophysiological disturbances constitutes the basis of functional dyspepsia.

Adult↗

[Changes caused by mineral water on gastrointestinal motility in patients with chronic idiopathic dyspepsia].

BACKGROUND: The antidyspeptic property of mineral waters has been based for ages on empirical data. In the present paper the effects of one of them (Tettuccio, Montecatini) on gastrointestinal motility of patients with dyspepsia has been evaluated. METHODS: The study was carried out on 24 patients with idiopathic dyspepsia and delayed gastric emptying at scintigraphy and 18 healthy subjects with normal gastric emptying. The gastric emptying of this mineral water was studied with a scintigraphic method in comparison with tap water, while its effects on gastroduodenal contractions were evaluated by of manometry. RESULTS: The gastric emptying of this mineral water was significantly faster than that of tap water, both in dyspeptic patients and in normals. Manometric examination showed that the administration of mineral water induced a brief decrease of phasic motor activity, followed by a progressive increase, which in some cases ended in an activity front of the Migrating Motor Complex. CONCLUSIONS: This mineral water has a stimulating effect on both gastric emptying and interdigestive cyclic motor activity of the gastroduodenal tract. Both these effects could be useful in the treatment of chronic idiopathic dyspepsia and impaired gut clearing.

Adolescent↗

Gastrointestinal motility in space motion sickness.

Gastrointestinal (Gl) symptoms in space motion sickness (SMS) are significantly different from those in ordinary motion sickness (MS). Vomiting is sudden, often unexpected, infrequent, never prolonged and usually without nausea. Inflight bowel sounds are absent in those with SMS but present after recovery and in those not affected. Recording and tabulation of sounds was the only technique that could be used as a measure of motility during spaceflight operations. There were 17 subjects, 6 unaffected by SMS, who made ambulatory recordings pre- and inflight. With one exception, all those affected had sharply reduced sounds while those unaffected had increases or moderate reductions. The mechanism of vomiting in SMS appears to be secondary to this ileus in contrast to vomiting in ordinary MS, where the emesis center is thought to be directly triggered by the vestibular system. This ileus appears to be the only consistent and reliable indicator for SMS to date.

Auscultation↗

Measurement of gastrointestinal motility in the GI laboratory.

Current tests of gastric and small intestinal motor function provide relevant physiological information, but their clinical utility is controversial. This article reviews the current procedures, indications, significance, pitfalls, and guidelines for gastrointestinal motility measurements by scintigraphy, gastroduodenojejunal manometry, and surface electrogastrography in humans. Methods included review of literature and discussions in closed and open fora among investigators, including presentations for peer review at focused (Iowa City American Motility Society Symposium, December 1995) and national meetings (American Gastroenterological Association, May 1996, and American Motility Society, September 1996). The current tests are generally complementary; scintigraphy is typically the first test in the evaluation of gastric motor function and often confirms the clinical suspicion of dysmotility. Manometry identifies patterns suggestive of myopathy, neuropathy, or obstruction but may be most helpful when it shows entirely normal findings, because manometry helps in part to exclude dysmotility as a cause of symptoms. Electrogastrography may identify dysrhythmias or failure of signal power to increase postprandially; rhythm abnormalities may be independent of impaired emptying among dyspeptic patients. The best validated and clinically most significant results pertain to transit tests; manometry may contribute importantly to the diagnostic process; and the significance of electrogastrography remains to be fully elucidated.

Digestive System↗