After the discovery of motilin in 1972, motilin and the motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution - with the use of knockout models - sparked novel insights into the role of multiple peptides but contributed to a decline in interest in motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.

To review the human and veterinary literature regarding gastrointestinal (GI) dysmotility disorders in respect to pathogenesis, patient risk factors, and treatment options in critically ill dogs and cats.

GI dysmotility is a common sequela of critical illness in people and small animals. The most common GI motility disorders in critically ill people and small animals include esophageal dysmotility, delayed gastric emptying, functional intestinal obstruction (ie, ileus), and colonic motility abnormalities. Medical conditions associated with the highest risk of GI dysmotility include mechanical ventilation, sepsis, shock, trauma, systemic inflammatory response syndrome, and multiple organ failure. The incidence and pathophysiology of GI dysmotility in critically ill small animals is incompletely understood.

A presumptive diagnosis of GI dysmotility is often made in high-risk patient populations following detection of persistent regurgitation, vomiting, lack of tolerance of enteral nutrition, abdominal pain, and constipation. Definitive diagnosis is established via radioscintigraphy; however, this diagnostic tool is not readily available and is difficult to perform on small animals. Other diagnostic modalities that have been evaluated include abdominal ultrasonography, radiographic contrast, and tracer studies.

Therapy is centered at optimizing GI perfusion, enhancement of GI motility, and early enteral nutrition. Pharmacological interventions are instituted to promote gastric emptying and effective intestinal motility and prevention of complications. Promotility agents, including ranitidine/nizatidine, metoclopramide, erythromycin, and cisapride are the mainstays of therapy in small animals.

The development of complications related to GI dysmotility (eg, gastroesophageal reflux and aspiration) have been associated with increased mortality risk. Institution of prophylaxic therapy is recommended in high-risk patients, however, no consensus exists regarding optimal timing of initiating prophylaxic measures, preference of treatment, or duration of therapy. The prognosis for affected small animal patients remains unknown.

A proportion of patients with foregut dysmotility fail to respond to standard interventions. Motilin agonists may be beneficial in this group. We aimed to determine the effect of camicinal, a novel motilin agonist, on gastrointestinal physiology in healthy volunteers.

Healthy male subjects were randomly assigned to receive a single dose of 125 mg camicinal or placebo in a double-blind cross-over design. Esophageal function and reflux indices were assessed using high-resolution manometry (pre and 1.5-h post dose) and 24-h ambulatory multichannel intraluminal impedance/pH. After a standardized meal, subjects ingested a wireless motility capsule from which compartmental transit times and motility indices were derived. Subjects were restudied with the alternate intervention after 7 days.

The study subjects (12 male, mean age 47.4 years, range 22-55) tolerated the drug well, except one who exhibited mild abdominal pain on both placebo and camicinal. In comparison to placebo, gastric emptying time (GET) was accelerated following camicinal (-115.4 min, 95% confidence interval -194.4, -36.4, p = 0.009). No effect was demonstrable on esophageal function, small bowel, colonic, or whole bowel transit times and motility indices. With camicinal, as part of a post hoc analysis, there was a trend association between the percentage reduction in GET and total number of acidic reflux events (r = 0.56, p = 0.09).

Camicinal decreases GET and was generally well-tolerated. In health, the direct effects of camicinal are on accelerating GET with a potential secondary benefit of reducing reflux events, which warrant further exploration in patient cohorts.

Motilin agonists promote human gastric motility and cholinergic activity, but excitatory and inhibitory actions are reported in the esophagus. The effect of 5-HT₄ agonists in esophagus is also unclear. Perhaps the use of drugs with additional actions explains the variation. The aim, therefore, was to examine how motilin and prucalopride, selective motilin and 5-HT₄ receptor agonists, modulate neuromuscular functions in human esophagus and gastric fundus.

Electrical field stimulation (EFS) evoked nerve-mediated contractions of circular and longitudinal muscle from human esophageal body and circular muscle from gastric fundus.

In esophageal circular muscle EFS evoked brief contraction, followed by another contraction on termination of EFS, each prevented by atropine. Nitric oxide synthase inhibition facilitated contraction during EFS and the overall contraction became monophasic. In esophagus longitudinal muscle and gastric fundus, EFS evoked cholinergically mediated, monophasic contractions, attenuated by simultaneous nitrergic activation. Motilin (100-300 nM) reduced esophagus circular muscle contractions during EFS, unaffected by L-NAME or apamin. Motilin 300 nM also reduced EFS-evoked contractions of longitudinal muscle. Similar concentrations of motilin facilitated cholinergic activity in the fundus and increased baseline muscle tension. Prucalopride facilitated EFS-evoked contractions in esophagus (tested at 30 μM) and fundus (0.1-30 μM).

Selective motilin and 5-HT₄ agonists have different, region-dependent abilities to modulate human esophageal and stomach neuromuscular activity, exemplified by weak inhibition (motilin) or excitation (5-HT₄) in esophageal body and excitation for both in stomach. In different patients with motility dysfunctions, motilin and 5-HT₄ agonists may reduce gastro-esophageal reflux in different ways.

This paper presents commentaries on whether Starling's law applies to the esophagus; whether erythromycin affects esophageal motility; the relationship between hypertensive lower esophageal sphincter and vigorous achalasia; whether ethnic- and gender-based norms affect diagnosis and treatment of esophageal motor disorders; health care and epidemiology of chest pain; whether normal pH excludes esophageal pain; the role of high-resolution manometry in noncardiac chest pain; whether pH-impedance should be included in the evaluation of noncardiac chest pain; whether there are there alternative therapeutic options to PPI for treating noncardiac chest pain; and the usefulness of psychological treatment and alternative medicine in noncardiac chest pain.

The gastrointestinal tract is a complex organ system. Dysfunctions of this organ system may evoke a variety of consequences for the entire organism and influence the inflammatory response in particular. In perioperative medicine, nutrition, prokinetics, peridural anesthesia, catecholamines and volume therapy can be applied in order to improve the gastrointestinal functional or at least to avoid further aggravation. Early enteral nutrition is especially important in the reduction of postsurgical ileus and infectious complications. Also, prokinetics and thoracic peridural anesthesia favorably affect postsurgical ileus. Norepinephrine, if necessary in combination with dobutamine, seems to have fewer negative effects on splanchnic perfusion than epinephrine. The data on volume therapy remain controversial but fluid balance has to be calculated very carefully also considering enteral loss of fluids. Thus, in order to treat and avoid gastrointestinal problems after surgery and to prevent negative effects for the complete organism, multimodal concepts with regard to detail are required.

This article highlights current and emerging pharmacological treatments for gastroesophageal reflux disease (GERD), opportunities for improving medical treatment, the extent to which improvements may be achieved with current therapy, and where new therapies may be required. These issues are discussed in the context of current thinking on the pathogenesis of GERD and its various manifestations and on the pharmacologic basis of current treatments.

Previous studies have established the presence of a postprandial acid pocket at the gastro-oesophageal junction.

To investigate whether altering gastric motility would affect the location and the extent of postprandial acid pockets in healthy volunteers and also to study the presence of bile in this pocket.

A total of 16 healthy volunteers underwent pH and Bilitec probe stepwise pull-through to measure regional differences in pH and bile absorbance before and 10, 30 and 50 min after a liquid meal. At the start of the meal, saline, erythromycin or sumatriptan was administered.

After saline, ingestion of a meal induced an acid pocket, with a mean pH drop of 2.26 (compared to 0.25 before the meal, P < 0.05) and a nadir pH of 2.71. The acid pocket persisted 30 and 50 min postprandially (pH drops 1.59 and 1.68 and nadir pH 3.17 and 2.52 respectively). Compared with saline, erythromycin significantly suppressed the pH drop and nadir pH (on average 0.66 and 3.4 at 10 min; comparable patterns at 30 and 50 min). After sumatriptan a significantly lower nadir pH was observed at 30 and 50 min (respectively 2.02 and 1.74, P < 0.05 compared with saline). A postprandial bile pocket was noted in 50% of pull-throughs after saline, compared to 78% after erythromycin and 31% after sumatriptan.

The presence of a bile pocket in a subset of the subjects confirms the heterogeneity of postprandial intragastric contents. Erythromycin disrupts the acid pocket but increases the presence of bile, while sumatriptan has opposite effects.

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties.

This article highlights current and emerging pharmacological treatments for gastroesophageal reflux disease (GERD), opportunities for improving medical treatment, the extent to which improvements may be achieved with current therapy, and where new therapies may be required. These issues are discussed in the context of current thinking on the pathogenesis of GERD and its various manifestations and on the pharmacologic basis of current treatments.

Motilin, an endogenous gastrointestinal (GI) hormone, increases upper gastrointestinal tract motility and is associated with phase III of the gastric migrating motor complex. The motilin receptor agonist, atilmotin, at doses of 6, 30 or 60 microg intravenously (IV), increases the early phase of gastric emptying. Prior studies at higher doses of 100-450 microg IV demonstrated that some subjects developed noncardiac chest pain.

The aim of this study is to determine the effects of atilmotin on esophageal, lower esophageal sphincter (LES), and gastric contractility and the development of esophageal-related symptoms.

Ten healthy volunteers underwent esophageal manometry to study the effects of atilmotin on upper GI motility. Five subjects were studied on three separate days following administration of saline placebo and subsequent IV bolus dose of atilmotin (6, 30 or 150 microg). Another five subjects were studied at the highest dose (150 microg).

Atilmotin at 150 microg increased proximal gastric pressure by 6.5 mmHg (P = 0.001 compared with placebo). Atilmotin increased LES pressure at all studied doses; LES pressure increased from 24 +/- 2 mmHg following placebo injection to 34 +/- 4 mmHg following a 30 microg dose of atilmotin (P = 0.007). In the esophagus, atilmotin increased the percentage of failed swallows at the highest dose studied. Failed swallows increased from 17 +/- 7% following placebo injection to 36 +/- 7% following a 150 microg dose of atilmotin (P = 0.016). Atilmotin decreased distal esophageal contractile amplitude only at the highest dose studied, from 69 +/- 8 mmHg (placebo) to 50 +/- 5 mmHg following 150 microg atilmotin (P = 0.018). There were no serious adverse effects or episodes of chest pain with atilmotin.

Atilmotin affects esophageal, LES, and gastric motility. LES and gastric pressures were increased, whereas there was disruption of esophageal peristalsis characterized by lower amplitude and failed contractions.

Enteral feeding is often limited by gastric and intestinal motility disturbances in critically ill patients, particularly in patients with shock. So, promotility agents are frequently used to improve tolerance to enteral nutrition. This review summaries the pathophysiology, presents the available pharmacological strategies, the clinical data, the counter-indications and the principal limits. The clinical data are poor. No study demonstrates a positive effect on clinical outcomes. Metoclopramide and erythromycin seems to be the more effective. Considering the risk of antibiotic resistance, the first line use of erythromycin should be avoided in favor of metoclopramide.

Inhibition of gastrointestinal motility is a major problem in critically ill patients. Motor stasis gives rise to subsequent complications including intolerance to enteral feeding, enhanced permeability of the atrophic intestinal mucosa and conditions as severe as systemic inflammatory response syndrome, sepsis and multiple organ failure. Although the diagnosis of motility disturbances in critically ill patients is difficult, the type and site of the disturbance are important to consider in the analysis of the condition and in the choice of therapeutic approach. The pharmacological treatment of impaired gastrointestinal motility is difficult to handle for the clinician, because the underlying mechanisms are complex and not fully understood and the availability of pharmacological treatment options is limited. In addition, there is a lack of controlled studies on which to build an evidence-based treatment concept for critically ill patients. Notwithstanding this situation, there has been remarkable progress in the understanding of the integrated regulation of gastrointestinal motility in health and disease. These advances, which largely relate to the organization of the enteric nervous system and its signaling mechanisms, enable the intensivist to develop a standardized concept for the use of prokinetic agents in the treatment of impaired gastrointestinal motility in critically ill patients.

In this double-blind cross-over study, we assessed whether erythromycin infusion is effective as a prokinetic drug against gastroparesis from acute pain. The effect of erythromycin on gastric emptying (GE) was measured in seven volunteers subjected to a standardized acute painful stimulus. The GE rate for solids was measured using the octanoic acid breath test. An acetaminophen absorption test measured the GE rate for liquids. Five minutes after ingestion of a 13C-labeled meal, the subjects received in randomized order either a test (placebo and erythromycin groups) or a control (control group) stimulus consisting of repeated 1-min immersion of a hand into 4 degrees C (test) or 37 degrees C (control) water, with 15 s for recovery between immersions, for a total of 20 min. While the stimulus was applied, 250 mL saline (control and placebo groups) or 250 mg erythromycin (erythromycin group) was infused. Pain and stress were evaluated using visual analog scales, and standard hemodynamic values were recorded throughout the study. Our results show that acute stress decreased GE for solids, which was significantly accelerated in the erythromycin group in comparison with the placebo group. GE for liquids was similar in the three groups. We conclude that erythromycin is effective as a prokinetic drug for solids in acute painful situations.

Gastrointestinal promotility drugs stimulate smooth muscle contractions to enhance gastric emptying and small and large bowel transit. Currently available drug classes with prokinetic properties include antidopaminergic agents, serotonergic agents, and motilin-receptor agonists. Due to moderate prokinetic effects, poor symptomatic responses and the presence of adverse effects, there is a clear need for new classes of prokinetics. Several newer prokinetic drugs and drug classes are currently under evaluation. Selecting candidate agents and designing the appropriate therapeutic trials is hampered by the lack of insight in the pathophysiology of motility-related symptoms. As gastrointestinal motor disorders are chronic, relapsing, and remitting disorders, it seems desirable that studies with candidate prokinetic drugs establish a long-term efficacy and not only short-term effects on gastrointestinal functions.

We studied effects of i.v. atilmotin (BAX-ACC-1638, a novel motilin agonist, circulating t(1/2) < 10 min) on gastrointestinal transit in humans using a randomized, parallel-group, dose-response double-blind study of i.v. atilmotin, 6, 30, 60 microg or vehicle (placebo) given 2 min after standardized breakfast, lunch and dinner. The breakfast meal contained (99m)Tc-eggs and (111)In-milk. Full gastrointestinal transit was measured by scintigraphy. Primary endpoints were % gastric emptying (GE) at 30 min, GE t(1/2), colonic filling (CF) at 6 h, and geometric centre of colonic transit at 24 h. Analysis included adjustment for age, gender and body mass index, with Bonferroni correction applied for multiple comparisons. A significant treatment effect of atilmotin was detected for GE (%) at 30 min for solids and liquids (P < 0.01 for both). There were no significant effects on CF or CT and no significant adverse clinical events. Thus, atilmotin accelerates GE of solids and liquids in healthy humans. These data suggest that, at the doses tested, atilmotin should be considered for treatment of stomach motility disorders.

The role of the sphincter of Oddi (SO) in ethanol (ETOH)-induced pancreatitis is controversial. Our aim was to characterise the effect of ETOH on basal and stimulated SO motility.

SOs removed from white rabbits were placed in an organ bath (Krebs solution, pH7.4, 37 degrees). The effects of 2 mL/L, 4 mL/L, 6 mL/L and 8 mL/L of ETOH on the contractile responses of the sphincter were determined. SOs were stimulated with either 0.1 mumol/L carbachol, 1 mumol/L erythromycin or 0.1 mumol/L cholecystokinin (CCK).

ETOH at a dose of 4 mL/L significantly decreased the baseline contractile amplitude from 11.98+/-0.05 mN to 11.19+/-0.07 mN. However, no significant changes in the contractile frequency were observed. ETOH (0.6%) significantly decreased both the baseline amplitude and the frequency compared to the control group (10.50+/-0.01 mN, 12.13+/-0.10 mN and 3.53+/-0.13 c/min, 5.5+/-0.13 cycles(c)/min, respectively). Moreover, 0.8% of ETOH resulted in complete relaxation of the SO. Carbachol (0.1 micromol/L) or erythromycin (1 micromol/L) stimulated the baseline amplitudes (by 82% and 75%, respectively) and the contractile frequencies (by 150% and 106%, respectively). In the carbachol or erythromycin-stimulated groups 2-6 mL/L of ETOH significantly inhibited both the amplitude and the frequency. Interestingly, a 4-5 min administration of 0.6% ETOH suddenly and completely relaxed the SO. CCK (0.1 micromol/L) stimulated the baseline amplitude from 12.37+/-0.05 mN to 27.40+/-1.82 mN within 1.60+/-0.24 min. After this peak, the amplitude decreased to 17.17+/-0.22 mN and remained constant during the experiment. The frequency peaked at 12.8+/-0.2 c/min, after which the constant frequency was 9.43+/-0.24 c/min throughout the rest of the experiment. ETOH at a dose of 4 mL/L significantly decreased the amplitude from 16.13+/-0.23 mN to 14.93+/-0.19 mN. However, no significant changes in the contractile frequency were observed. ETOH at a dose of 6 mL/L inhibited both the amplitudes and the frequencies in the CCK-stimulated group, while 8 mL/L of ETOH completely relaxed the SO.

ETOH strongly inhibits the basal, carbachol, erythromycin, and CCK-stimulated rabbit SO motility. Therefore, it is possible that during alcohol-intake the relaxed SO opens the way for pancreatic fluid to flow out into the duodenum in rabbits. This relaxation of the SO may protect the pancreas against alcohol-induced damage.

It has previously been demonstrated that clasp and sling fibers at the human gastroesophageal junction respond differently to acetylcholine (Ach). The present study was undertaken to investigate the differences between the physiological and pharmacological properties of the two types of muscle fiber.

Recordings were made of the isometric tension of human sling and clasp fibers in response to Ach, dopamine (DA), phenylephrine (Phe), and isoprenaline (Iso). These specimens were obtained from 18 patients who were operated on for esophageal cancer.

Both Ach and Phe increased the tension of the two types of muscle; the values in the Ach group being 3-4-fold greater than those in the Phe group, while Iso decreased the tension of both types of muscle strip. The tension of the sling fibers was reduced by DA at lower concentration, and then increased gradually as the concentration was increased. In contrast, the tension of the clasp fibers did not obviously change when the concentration of DA was lower, but a slow elevation of tension was seen with the increase in DA concentration.

The sensitivities and maximum responses to each agent differed between the clasp fibers and sling fibers. This suggests that the two kinds of fiber have different roles in establishing tension in the lower esophageal sphincter, with implications for the medical and surgical treatment of disorders in this region.

Recent combined manometric-barostat studies demonstrated that the oesophageal body exhibits both peristaltic contractions and tone. This study further characterized the neural modulation of tone in the feline oesophageal body. Simultaneous oesophageal barostat and manometry were performed in 20 adult cats under ketamine sedation. Oesophageal tone and peristalsis were assessed in the distal smooth muscle oesophagus. Cholinergic modulation was studied using neostigmine, erythromycin, atropine and vagotomy. Nitrergic regulation was assessed using sildenafil to increase cellular cyclic guanosine monophosphate and the nitric oxide synthase blocker Nomega-nitro-l-arginine (l-NNA). The presence of a tonic contractile activity in the distal oesophageal body was confirmed. Peristaltic contractions proceeded along the oesophageal body over the background tonic contraction. Neostigmine and erythromycin enhanced (20-30%) whereas bilateral vagotomy and atropine strongly decreased oesophageal tone (50-60%). However, l-NNA increased (40%) and sildenafil decreased oesophageal tone (30%). Therefore, tonic contractile activity in the oesophageal body is mainly caused by a continuous cholinergic excitatory input. A nitric oxide inhibitory mechanism may have a complementary role in the regulation of oesophageal tone.

The role of fundic tension and stretch mechanoreceptors in triggering transient lower esophageal sphincter (LES) relaxation is still unknown. This information would be useful for the development of effective pharmacologic strategies. To elucidate this topic, gastric contractile activity was modified during isovolumetric gastric distention at 2 different volumes.

LES (Dentsleeve) and gastric (barostat) motility were recorded in 21 healthy subjects during studies comprising two 30-minute isovolumetric gastric distentions (placebo and glucagon or erythromycin). Glucagon (bolus of 4.8 microg/kg plus infusion of 9.6 microg x kg(-1) x h(-1)) was administered at high intragastric volume (i.e., 75% of the threshold volume for discomfort; n = 7) and erythromycin (3 mg/kg) at high (n = 7) and low intragastric volume (i.e., at perception threshold; n = 7).

Glucagon decreased (P < 0.05) baseline intragastric pressure and abolished gastric contractions (0 vs. 16.7 +/- 2.3), whereas erythromycin increased (P < 0.05) baseline pressure and doubled (P < 0.05) the rate of gastric contractions at both volumes. Neither drug affected the rate of transient LES relaxations. Low intragastric volume induced a lower rate of transient LES relaxations (1.7 +/- 0.3 vs. 5.7 +/- 1.1; P < 0.01) and gastric contractions (11.8 +/- 2.5 vs. 20.5 +/- 3.1; P < 0.05) compared with high volume but similar baseline intragastric pressure (10.6 +/- 0.6 vs. 11.9 +/- 0.9 mm Hg).

Stretch receptors (gastric volume) seem to be more relevant than tension receptors in triggering transient LES relaxation.

The effect of ABT-229, a new macrolide with no antibacterial activity, on gastro-oesophageal reflux, oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease was investigated.

Twenty-one patients were treated with a placebo and ABT-229 (2.5, 5 or 10 mg b.d.) in a randomized, incomplete crossover study design. Ambulatory 24-h pH manometry was performed and gastric emptying was assessed by the 13C-octanoic acid breath test on the seventh day of treatment.

A significant decrease was found in the mean (+/- s.e.) percentage of reflux time (intra-oesophageal pH < 4) for ABT-229 5 mg b.d. and 10 mg b.d., but not for 2.5 mg b.d., compared with placebo. For ABT-229 5 mg, it was 8.5 +/- 0.5% vs. 10.7 +/- 0.7% (P < 0.038) and, for ABT-229 10 mg, it was 6.6 +/- 0.5% vs. 8.4 +/- 0.5% (P < 0.019). There were no significant differences in any of the analysed manometric parameters. In addition, the gastric half-emptying time for all doses of ABT-229 did not differ significantly from that after placebo.

ABT-229 is able to reduce slightly, but significantly, acid reflux in patients with gastro-oesophageal reflux disease. This effect does not appear to be due to a measurable improvement in oesophageal motility or gastric emptying.

Erythromycin exhibits gastrokinetic properties through cholinergic pathways. Reports regarding the action of octreotide on gastric emptying are conflicting.

: To assess: (i) the hypothesis that serotonin receptors are involved in the accelerating effect of erythromycin on gastric emptying; and (ii) any modification of the gastrokinetic action of erythromycin induced by octreotide.

Gastric emptying of a standard meal was estimated in 20 healthy subjects by scintigraphy on three different occasions in a double-blind, placebo-controlled manner and in random order: (i) after placebo; (ii) after 200 mg of intravenous erythromycin; and (iii) after 200 mg of intravenous erythromycin following pre-treatment with either 4 mg of intravenous ondansetron (10 subjects) or 50 micro g octreotide.

Erythromycin significantly accelerated gastric emptying in all subjects by abolishing the lag phase. Pre-treatment with ondansetron abolished the accelerating effect of erythromycin by restoring the emptying times to placebo levels. Octreotide significantly enhanced the accelerating effect of erythromycin by reducing both the lag and post-lag phases of gastric emptying.

Serotonin receptors are involved in the accelerating effect of erythromycin on gastric emptying. This effect seems to be enhanced by pre-treatment with octreotide, possibly as a result of the modification of the gastrointestinal hormonal environment.

As clarithromycin (CLA), an antibiotic commonly used for Helicobacter pylori eradication, stimulates gastroduodenal motility, we investigated whether it also stimulates esophageal motility. In 15 normal subjects, esophageal motility was recorded using a low-compliance manometric system with two ports in the esophageal body, one port in the lower esophageal sphincter (LES), and five ports in the antroduodenal tract to monitor the occurrence of phases I-III of the migrating motor complex. Thirty minutes after the occurrence of a duodenal phase III, we infused intravenously, randomly, and in a double-blind manner, CLA 100 mg in five subjects (group A), CLA 250 mg in five subjects (group B), and normal saline in the remaining five subjects (group C). LES tone and post-deglutitive residual pressure, as well as the amplitude and duration of the esophageal contractions, were measured each minute and averaged over a post-infusion period of 30 min. Both group A and B showed a LES tone significantly higher than that of group C after CLA infusion, whereas the post-deglutitive residual pressure was not significantly different from that of group C. The LES tone of group B was significantly higher than that of group A. Group B, but not group A, showed a wave amplitude and duration significantly higher than that of group C. In conclusion, CLA is able to stimulate LES tone and esophageal contractions with a dose-related effect.

Intravenous (i.v.) erythromycin enhances gastric emptying and oesophageal motility in both healthy and disease situations, acting either as a motilin or acetylcholine agonist. The purpose of the present paper was to investigate any possible effect of i.v. erythromycin on oesophageal motility in patients with gastro-oesophageal reflux (GOR).

In 15 patients with GOR (proven on 24-h ambulatory oesophageal pH measurement), standard oesophageal manometry was performed after i.v. injection of placebo and 200 mg erythromycin, in a random blind fashion.

Erythromycin significantly increased lower oesophageal sphincter (LOS) pressure from 17 +/- 5 to 41 +/- 10 mmHg (P < 0.001), without affecting the postdeglutition relaxation of LOS. Erythromycin also increased the amplitude (from 79 +/- 34 to 97 +/- 40 mmHg; P < 0.001), duration (from 3.4 +/- 0.6 to 3.8 +/- 0.6 s; P = 0.005), velocity (from 3.1 +/- 0.8 to 3.5 +/- 1.15 cm/s; P = 0.0047) and strength (from 149 +/- 84 to 201 +/- 103 mmHg.s; P < 0.001) of peristalsis at 5 cm proximal to the LOS. Similarly, the drug increased the amplitude of peristalsis at 10 and 15 cm proximal to the LOS (from 70 +/- 39 to 77.4 +/- 37 mmHg; P = 0.049 and from 36 +/- 20 to 49 +/- 36 mmHg; P = 0.004, respectively) and the duration of peristalsis at the same levels (from 3.1 +/- 0.6 to 3.3 +/- 0.5 s; P = 0.011, and from 2.7 +/- 0.6 to 3 +/- 0.5 s; P = 0.003, respectively).

Intravenously administered erythromycin improves impaired oesophageal motility in patients with GOR. This observation might be of clinical use.

Erythromycin exhibits prokinetic properties. The drug enhances esophageal and gastric motility by acting as a motilin agonist and promoting acetylocholine release. 5-HT3 receptors are involved in the spontaneously occurring migrating motor complex and the effect of erythromycin on antral motility in dogs. The aim of the study was to investigate the hypothesis that 5-HT3 receptors are also involved in the action of erythromycin on the human esophagus.

A total of 18 healthy volunteers underwent standard esophageal manometry on three different occasions in a double-blind, placebo-controlled, randomized manner, as follows: 1) after placebo, 2) after 200 mg of erythromycin i.v., and 3) after 200 mg of i.v. erythromycin subsequent to pretreatment with either 4 mg of i. v. ondansetron (serotonin receptor antagonist) (10 subjects) or 12 microg/kg of i.v. atropine (8 subjects).

Erythromycin significantly increased a) the amplitude of peristalsis at 5 cm (from 87 +/- 19 mm Hg to 108 +/- 26 mm Hg; p = 0.0007), 10 cm (from 72 +/- 24 mm Hg to 81 +/- 26 mm Hg; p = 0.016), and 15 cm (from 47 +/- 15 mm Hg to 55 +/- 17 mm Hg; p = 0.014) proximal to LES, b) the duration of peristalsis at 5 cm (from 4.5 +/- 0.9 s to 5.7 +/- 1.2 s; p < 0.0001) and 10 cm (from 4.1 +/- 1 s to 4.9 +/- 1 s; p < 0.0001) proximal to the LES and c) the strength of peristalsis at 5 cm proximal to the LES (from 180 +/- 49 mm Hg x s to 276 +/- 100 mm Hg x s; p < 0.0001), and decreased the velocity of peristalsis at distal esophagus (from 4.1 +/- 1 cm/s to 3.8 +/- 0.9 cm/s; p = 0.03). In addition, erythromycin significantly increased the resting pressure of the LES (from 36 +/- 10 mm Hg to 44 +/- 12 mm Hg; p = 0.002). Pretreatment with ondansetron totally reversed all of the effects of erythromycin to the placebo state. Pretreatment with atropine not only prevented the effects of erythromycin, but it reduced the amplitude and strength of peristalsis at the distal esophagus at significantly lower levels than after placebo.

Erythromycin exerts its prokinetic action on the lower esophagus by stimulating cholinergic pathways. This action includes not only an increase in LES pressure, but significant increases in the amplitude and duration of esophageal peristalsis, as well. 5-HT3 receptors are also involved in this process.

ABT-229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans.

To investigate the effect of oral treatment with ABT-229 10 mg b.d., ABT-229 5 mg b. d. and cisapride 10 mg q.d.s. on gastro-oesophageal reflux, lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations and symptoms in GERD patients.

Twenty-four GERD patients completed the study. A randomized, double-blind, placebo-controlled, three-period incomplete crossover design was used with three dosing periods of 7 days. All patients received ABT-229 10 mg b.d. and placebo during two of the three periods. In the remaining period 12 patients were given ABT-229 5 mg b.d. and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures were performed on day 7 using an assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system.

Oesophageal acid exposure was not affected by ABT-229 or cisapride, but the incidence of reflux episodes was reduced by cisapride. None of the drugs affected oesophageal motility, lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations. Both ABT-229 10 mg b.d. and cisapride reduced the severity of daytime heartburn.

The value of ABT-229 in the treatment of GERD appears to be limited.

Functional gut disorders include several clinical entities defined on the basis of symptom patterns (e.g., functional dyspepsia, irritable bowel syndrome, functional abdominal pain, functional abdominal bloating), for which there is no established pathophysiological mechanism. Because there is no well-defined pathophysiological target, treatment should be aimed at symptom improvement. Prokinetics and antispasmodics have been widely used in the treatment of functional gut disorders on the assumption that disordered motility is the underlying cause of symptoms, and symptom improvement is indeed achievable with these compounds in some, but not all, patients with features of hypo- or hypermotility, respectively. In the first part of this review, we cover the basic pharmacology and discuss the rationale for the clinical use of prokinetics and antispasmodics. On the other hand, in the past few years, the explosive growth in the research focusing on visceral sensitivity and visceral reflexes has suggested that at least some patients with functional gut disorders have altered visceral perception. Thus, the second part of the review covers these developments and focuses on studies addressing the issue of drugs modulating visceral sensitivity.

The macrolide antibiotic erythromycin (EM) affects gastrointestinal motor activity by acting as agonist of motilin receptors located on the smooth muscle cells of the gastroduodenal tract. We studied the effect of intravenous EM on fasting antroduodenal motility in controls and children with gastrointestinal dysmotility.

EM lactobionate (rate, 3.0 mg/kg/h) was infused intravenously while antroduodenal manometry was recorded in 10 controls, in 7 patients with functional dyspepsia and in 6 patients with gut pseudo-obstruction. The mean (SD) age (years) was 5.7 (1.4), 6.5 (2.4), and 6.7 (3.2), respectively. Manometry was performed by means of a four- or six-lumen catheter introduced through the nose and perfused with a low compliance pneumohydraulic system. Five controls received EM and five received saline.

EM, infused 5 minutes after passage of an activity front (AF), induced in controls a premature antroduodenal AF occurring 15.4 +/- 3.2 minutes after starting infusion; no motor changes were seen after saline; duration and propagation velocity of EM-induced AFs did not differ from spontaneous AFs. In patients with functional dyspepsia EM induced various patterns such as premature antroduodenal AFs, antral phase III-like pattern with short duodenal bursts or prolonged phasic antral waves and no duodenal activity. In patients with neurogenic pseudo-obstruction rare or absent antral activity with incoordinated or absent duodenal activity was induced; no contractions were elicited in two patients with myogenic pseudo-obstruction.

It is confirmed that EM, given at subtherapeutic doses, is a powerful prokinetic agent that can have clinical applications in patients with gastrointestinal dysmotility; however, the effect of the drug seems to be influenced by the nature of the underlying disorder.

Gastrointestinal motility is regulated by a complex balance of inhibitory and excitatory neuronal, humoral, and mechanical factors. The goal in the management of motility disorders is to maintain adequate nutrition while decreasing symptoms. This can be accomplished by medications and support of nutrition and biofeedback; the application of these therapeutic strategies to patients with gut motility disorders is reviewed.

EM523, a motilin agonist, is intended to be used as a gastroprokinetic during the postprandial period, but the mechanism(s) by which EM523 stimulates postprandial contractions in the stomach has not been studied before. The aim of this study was to examine the mechanism of contraction-stimulating activity by EM523 in fed dogs.

Contractile activity in the gastric antrum of 5 dogs was monitored using a long-term implanted force transducer and measured by integrating the area under the curve. Test materials were continuously infused or injected intravenously.

EM523 (1-30 micrograms/kg) induced a dose-dependent increase in fed-type contractions. EM523-induced contractile activity was partially inhibited by atropine, hexamethonium, dopamine, 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, and substance P antagonist. Atropine-resistant and EM523-induced contractions were further inhibited by 5-HT3 receptor antagonist and substance P antagonist, and the combined use of the two antagonists completely eliminated the atropine-resistant and EM523-induced contractions.

EM523-induced contractions in the fed stomach are quite different from phase III contractions in the fasted state and are mediated partially through the cholinergic pathway. The noncholinergic pathway involves 5-HT3 and neurokinin 1 receptors.

Although calcium plays an essential role in intestinal smooth muscle contractile activity, calcium entry pathways in canine and human small intestine are largely unknown. The goal of this study was to characterize calcium channels, a potential entry pathway for calcium, in isolated circular smooth muscle cells of canine and human jejunum.

Single freshly dissociated human and canine jejunal circular smooth muscle cells were studied using single-channel and perforated whole-cell patch clamp recordings as well as fluorescence dual wavelength ratio imaging.

An inward whole-cell current was identified that was carried by a 17 pS (80 mmol/L Ba2+) dihydropyridine-sensitive, barium-permeable channel. The current was potentiated by BayK 8644 (1 mumol/L; n = 3; 82% +/- 34%), acetylcholine (1 mumol/L; n = 8; 42% +/- 5%), and erythromycin (1 mumol/L; n = 9; 70% +/- 11%) and was completely blocked by nifedipine (1 mumol/L; n = 6) or diltiazem (200 mumol/L; n = 4). Application of BayK 8644 (1 mumol/L), acetylcholine (1 mumol/L), or erythromycin (1 mumol/L) to Fura-2-loaded smooth muscle cells bathed in Krebs' solution containing 2.54 mmol/L calcium increased intracellular calcium levels.

A calcium entry pathway was identified in canine and human jejunal circular smooth muscle cells. The pathway was mediated by a dihydropyridine-sensitive calcium channel. The channel allowed the entry of significant amounts of calcium at physiological extracellular calcium concentration.

Low doses of erythromycin induce antral contractions and accelerate gastric emptying. However, the effect of erythromycin on the proximal stomach remains unknown. The aim of this study was to assess the effect and mechanism(s) of action of erythromycin on proximal gastric tone in humans.

Gastric tone was measured using an electronic barostat in two groups of 6 subjects both in the fasting state and after a 200-kcal meal. On different occasions, subjects received saline, atropine alone (6 micrograms.kg-1.h-1 for 30 minutes), erythromycin alone (1.5 mg/kg in the fasting state and 1.5 and 3.0 mg/kg in the postprandial state), and erythromycin plus atropine.

Low-dose (1.5 mg/kg) erythromycin enhanced fasting gastric tone, but only the 3.0-mg/kg dose reduced the duration of meal-induced relaxation (37 +/- 14 vs. 105 +/- 20 minutes; P < 0.01). Atropine did not change the fasting or postprandial gastric tone as well as the erythromycin-induced responses. Plasma motilin levels were unaffected by erythromycin infusion. No correlation was observed between gastric tone and plasma motilin or erythromycin levels.

Erythromycin enhances fasting and postprandial proximal gastric tone in humans by a mechanism that does not seem to involve endogenous motilin release or a cholinergic pathway.

Investigation into gastrointestinal irritation from the use of erythromycin lead to the discovery of the gastrointestinal motor effect of this antibiotic. Erythromycin and gastrointestinal peptide motilin share many similar gastrokinetic activities, and studies indicate that erythromycin mimics the effect of motilin through motilin receptor agonism. Since erythromycin is readily available for clinical use, it may offer an alternative therapeutic approach to gastroparesis and related conditions. Several analogs of erythromycin without antimicrobial activity are also shown to possess similar motor effects, thus termed "motilides". A growing number of motilides may expand our knowledge on gastrointestinal peptides.