Motilin-induced gastric contractions signal hunger in man.

RATIONALE: Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. OBJECTIVES: To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. FINDINGS: In fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (ß=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. CONCLUSIONS: Motilin-induced gastric phase III is a hunger signal from GIT in man.

The role of the 4''-hydroxyl on motilin agonist potency in the 9-dihydroerythromycin series.

The role of the erythromycin 4''-hydroxyl group has been explored on the motilin agonist potential in the 9-dihydroerythromycin series of motilides. The compounds show potencies 2- to 4-fold superior to the corresponding hydroxylated compounds. The relationship is maintained when the 9-hydroxyl is alkylated to generate the corresponding 4''-deoxy-9-O-acetamido-9-dihydroerythromycins. However, concomitant with this increase in potency is an increase in hERG inhibition.

9-Dihydroerythromycin ethers as motilin agonists--developing structure-activity relationships for potency and safety.

A series of derivatives of the amine of 9-dihydro-9-O-ethylamino-N-desmethyl-N-isopropyl erythromycin A derivatives were synthesized as motilin agonists. The compounds were developed for potency without showing antibacterial activity and inhibition of the hERG potassium channel. The formamide of the amide series was found to show the optimal combination of properties relative to carbamates, ureas, thioureas, and amines. This prompted an investigation of heterocyclic isosteres for the amide. In this series the triazole had the optimal combination of properties. From the study, two compounds met the criteria for detailed pharmacokinetic studies.

Effect of atilmotin, a motilin receptor agonist, on esophageal, lower esophageal sphincter, and gastric pressures.

BACKGROUND: 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. AIMS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Emerging drugs for chronic constipation.

Chronic constipation (CC) is one of the most common functional gastrointestinal disorders. CC is estimated to affect up to 27% of the North American population. Although not life-threatening, CC can have profoundly negatively affects on quality of life and result in significant economic burden in terms of both direct and indirect healthcare costs. Possible etiologies for CC include alterations in gastrointestinal motility and secretion. Research efforts in CC have begun to identify multifactorial and often overlapping etiologies including abnormalities in myenteric neurons, alterations in neurotransmitters and their receptors, and incoordination of the muscles of the pelvic floor or anorectum. CC may be influenced by genetic predisposition, environmental factors and stress. In this article, the safety and efficacy of traditional and emerging therapies for CC are examined.

The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study.

The motilin agonist, erythromycin, induces gastric phase III of the migrating motor complex, which in turn generates hunger peaks. To identify the brain mechanisms underlying these orexigenic effects, 14 healthy women participated in a randomized, placebo-controlled crossover study. Functional magnetic resonance brain images were acquired for 50 minutes interprandially. Intravenous infusion of erythromycin (40 mg) or saline started 10 minutes after the start of scanning. Blood samples (for glucose and hormone levels) and hunger ratings were collected at fixed timepoints. Thirteen volunteers completed the study, without any adverse events. Brain regions involved in homeostatic and hedonic control of appetite and food intake responded to erythromycin, including pregenual anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, amygdala, caudate, pallidum and putamen bilaterally, right accumbens, hypothalamus, and midbrain. Octanoylated ghrelin levels decreased, whereas both glucose and insulin increased after erythromycin. Hunger were higher after erythromycin, and these differences covaried with the brain response in most of the abovementioned regions. The motilin agonist erythromycin increases hunger by modulating neurocircuitry related to homeostatic and hedonic control of appetite and feeding. These results confirm recent behavioural findings identifying motilin as a key orexigenic hormone in humans, and identify the brain mechanisms underlying its effect.

Clinical trial: effect of mitemcinal (a motilin agonist) on gastric emptying in patients with gastroparesis - a randomized, multicentre, placebo-controlled study.

BACKGROUND: Mitemcinal is an orally active motilin agonist that could potentially improve gastric emptying. AIM: To investigate the effect of mitemcinal on gastric emptying in patients with idiopathic and diabetic gastroparesis. METHODS: In a randomized, double-blind design, 106 patients were randomized into four dosing regimens (22 to placebo and 21 each to mitemcinal 10 mg, 20 mg, 30 mg bid or 20 mg tid) for 28 days. A standardized scintigraphic gastric emptying test was performed at screening and again after completing the 4-week protocol. RESULTS: All doses of mitemcinal showed prokinetic activity. A significant improvement in meal retention at 240 min was noted even in the lowest dose group with the greatest improvement observed with 30 mg bid group (75% vs. 10% in placebo group). Diabetic patients responded better than the idiopathic subgroup. In diabetic patients, blood glucose at 1 h after a meal showed dose-dependent elevation. Although gastroparetic symptoms improved with both mitemcinal and placebo, the prominent placebo effect was not statistically exceeded by mitemcinal. Baseline scintigraphy results exhibited no clear correlation between the severity of gastroparetic symptoms and the status of gastric emptying. CONCLUSION: Mitemcinal is capable of accelerating gastric emptying in both diabetic and idiopathic patients with gastroparesis.

Mitemcinal (GM-611), an orally active motilin agonist, facilitates defecation in rabbits and dogs without causing loose stools.

The effects of mitemcinal (GM-611), an orally active motilin agonist, on defecation were investigated in rabbits and dogs. In normal rabbits, within 0-3 h of dosing, orally administered mitemcinal (2.5-10 mg kg(-1)) increased stool weight in a dose-dependent manner without causing loose stools. Sennoside (12-48 mg kg(-1)) also facilitated defecation within 2-9 h of oral administration, but the stools were significantly loosened. In the morphine-induced constipation model, the stool weight of morphine-treated rabbits (1 mg kg(-1)) was only 37.5% of that of untreated animals. Mitemcinal (0.5-20 mg kg(-1)) dose-dependently increased stool weight without increasing stool water content. At the highest dose of mitemcinal, stool weight recovered to 83.9% of that of untreated animals. In normal dogs, mitemcinal (0.3-3 mg kg(-1)) reduced the time to first bowel movement after oral administration without inducing diarrhoea at any dose. These results indicate that mitemcinal facilitates defecation without inducing severe diarrhoea. It is suggested that mitemcinal may be a novel therapeutic agent for constipation that enables easier control of the timing of defecation because of the early onset and short duration of its action, compared with sennoside.

Emerging drugs for postoperative ileus.

Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalization. Although the origin and cause of POI are poorly understood, it is known that abnormal GI motility associated with delayed gastric emptying and intestinal transit is a major factor leading to abdominal bloating, vomiting and lack of defecation. Furthermore, opioid drugs such as morphine, used for the management of postoperative pain, cause inhibition of bowel transit. Proposed mechanisms of POI include the stimulation of neuronal responses, such as excitation of afferent neurons and activation of noradrenergic, non-adrenergic and non-cholinergic neuronal pathways, as well as the induction of an intestinal inflammatory response. The development of new pharmacological strategies to prevent or reduce the frequency of POI is very important as existing approaches do not offer relief for most patients. This review describes emerging therapeutics that may advance the care of patients with POI.

The pharmacodynamics, safety and pharmacokinetics of single doses of the motilin agonist, camicinal, in type 1 diabetes mellitus with slow gastric emptying.

BACKGROUND AND PURPOSE: Here we have investigated the pharmacokinetics, pharmacodynamics and safety of single doses of camicinal in type 1 diabetes mellitus (T1DM) patients with a history of slow gastric emptying with symptoms consistent with gastroparesis. EXPERIMENTAL APPROACH: In a randomized, double-blind, placebo-controlled, incomplete block, three-period, two-centre crossover study, patients received oral administration of placebo and two of the three possible doses of camicinal (25, 50 or 125 mg). Gastric emptying ((13) C-octanoic acid breath test), pharmacokinetics and safety were primary outcomes. KEY RESULTS: Nine of the 10 patients enrolled completed the study. Gastric half-emptying time decreased by -95 min (95% CI: -156.8, -34.2) after a single dose of camicinal 125 mg compared with placebo (52 vs. 147 min, P < 0.05), representing a 65% improvement. A decrease of the gastric half-emptying time compared with placebo (approximately 39 min) was observed with camicinal 25 and 50 mg, representing a 27% reduction for both doses (not statistically significant). A positive exposure-response relationship was demonstrated across all doses. The effects of camicinal on gastric half-emptying time were not influenced by fasting glucose levels. Single doses up to 125 mg were well tolerated. Camicinal was well absorbed, exhibiting linear and approximately dose-proportional pharmacokinetic characteristics and a clear exposure-response relationship with gastric emptying. CONCLUSIONS AND IMPLICATIONS: Camicinal significantly accelerated gastric emptying of solids in T1DM patients following administration of a single oral dose. Camicinal was well tolerated and exhibited similar pharmacokinetic characteristics in diabetic patients to those previously reported in healthy volunteers.

The effects of camicinal, a novel motilin agonist, on gastro-esophageal function in healthy humans-a randomized placebo controlled trial.

BACKGROUND: 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. METHODS: 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. KEY RESULTS: 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). CONCLUSIONS & INFERENCES: 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.

Discovery of a potent and novel motilin agonist.

A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino acid derivatives were identified as very potent motilin receptor agonists. Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660 nM) was found to improve in vitro potency approximately 3000-fold, resulting in compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of 0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the binding assay. In addition, compound 11A was shown to have a significantly reduced tendency to cause receptor desensitization as compared with the motilin receptor agonist ABT-229.

The effect of motilin agonist ABT-229 on gastro-oesophageal reflux, oesophageal motility and lower oesophageal sphincter characteristics in GERD patients.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The value of ABT-229 in the treatment of GERD appears to be limited.

Effects of a new motilide, ABT-229, on gastric emptying and postprandial antroduodenal motility in healthy volunteers.

BACKGROUND: ABT-229 is a recently developed derivative of erythromycin, devoid of antibiotic activity. We studied the effect of ABT-229 on gastric emptying and postprandial antroduodenal motility in healthy volunteers. METHODS: Placebo, 4 and 16 mg ABT-229 were given as a single oral dose to nine healthy volunteers, in a randomized, 3-period crossover design. A solid meal (250 kcal) was given twice, 45 min after drug ingestion and 4 h later. Gastric emptying of each meal was studied using the 13C-octanoic breath test. Antroduodenal motility was recorded during the total 9-h period. RESULTS: After the first meal, both the 4 and 16 mg doses increased the gastric emptying rate to a similar extent. ABT-229 stimulated the contractile motility of the antrum dose-dependently. The half-emptying time and the lag-phase of gastric emptying correlated with the number of pressure waves that were propagated over the antrum and the mean amplitude of antral pressure waves. After the second meal no significant effects of ABT-229 were found. CONCLUSIONS: A single dose of the new motilin agonist ABT-229 strongly increases the gastric emptying rate in healthy volunteers by increasing the strength and length of propagation of antral pressure waves. ABT-229 has the potential to become a new prokinetic drug.

Effects of ABT-229, a motilin agonist, on acid reflux, oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease.

AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 stimulates gastric emptying after esophagectomy with gastric replacement: a randomized clinical trial.

UNLABELLED: Delayed gastric emptying after esophagogastrectomy can pose a significant early postoperative problem. Because erythromycin, which stimulates the gastric antral and duodenal motilin receptor, has been shown to significantly increase gastric emptying in patients with diabetic gastroparesis, we decided to evaluate its effect on gastric emptying after esophagogastrectomy. METHODS: Twenty-four patients (18 men and six women, age range 41 to 79 years, median 66 years) were randomized to receive either erythromycin lactobionate (200 mg in 50 ml normal saline solution intravenously) (n = 13) or placebo (50 ml normal saline solution intravenously (n = 11) 11 days after esophagogastrectomy (with pyloric drainage procedure). After erythromycin or placebo had been infused over a 15-minute period, patients ingested a solid meal (scrambled egg with bread) labeled with technetium 99m sulfur colloid (500 microCi) over approximately 15 minutes. Dynamic images of the stomach were then acquired over 90 minutes in the supine position by gamma imaging. Results were expressed as percentage of counts retained in the stomach (percent gastric retention) over time. RESULTS: There were no side effects of erythromycin. In the placebo group, the mean percent of radiolabeled meal retained in the stomach after 90 minutes was 88%, which was significantly greater than in the erythromycin group, 37% (p < 0.001). In addition, analysis of covariance demonstrated that the rate of gastric emptying (slope of the line) was significantly greater in the erythromycin-treated group than in the placebo group (p < 0.0001). CONCLUSION: Early satiety after esophagogastrectomy may be due to delayed gastric emptying and not due to a decrease in the gastric reservoir. Intravenous erythromycin significantly improves gastric emptying in patients after esophagogastrectomy by stimulating gastric motility.

Motilin and clinical application.

Motilin is a regulatory polypeptide of 22 amino acid residues and orginates in motilin cells scattered in the duodenal epithelium of most mammals and chickens. Motilin is released into the general circulation at about 100-min intervals during the interdigestive state and is the most important factor in controlling the interdigestive migrating contractions. Recent studies have revealed that motilin stimulates endogenous release of the endocrine pancreas. Clinical application of motilin as a prokinetic has become possible since erythromycin and its derivatives were proved to be nonpeptide motilin agonists.

EM523L, a nonpeptide motilin agonist, stimulates gastric emptying and pancreatic polypeptide secretion.

We investigated the efficacy and the mechanism of action of EM523L, a nonpeptide motilin agonist (motilide), on the stimulation of gastric emptying and on the release of gut peptides after ingestion of a solid meat in normal controls (n = 8) and in diabetic patients (n = 8) with signs of neuropathy. A dose of 2 mg EM523L was administered IV over 15 min just after ingestion of a solid meal (200 kcal Gastric emptying was measured by a radionuclide technique. EM523L accelerated gastric emptying and markedly augmented postprandial pancreatic polypeptide (PP) response in both normal control and diabetic patients. This may suggest the mediation of the Vagal-cholinergic pathway to accelerate gastric emptying. The present study offers a promising therapeutic potential of the motilide in gastrointestinal motility disorders like those observed in diabetics mellitus.

Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle.

The present study was undertaken to explore motilin's transduction pathway in the rabbit. Guanine nucleotides inhibited 125I-motilin binding in rabbit antral tissue and increased the dissociation of motilin from its receptor. Motilin, the motilin agonist erythromycin A enol ether (EM-201) and carbachol (taken as control) increased the production of inositol phosphates in rabbit duodenal smooth muscle strips labeled with myo-[2-3H]inositol. The effect of carbachol was blocked by atropine. Dose-response curves revealed that 50% of this effect was obtained with 3.9 nM motilin, 170 nM EM-201, 0.54 microM carbachol. Chromatographic separation of the inositol phosphate metabolites showed significant increases in the levels of [3H]inositol bisphosphate and of [3H]inositol trisphosphate. The three substances were without effect upon the metabolism of cAMP, nor did they modulate the rise in cAMP induced by GTP. We propose that motilin's transduction pathway uses a G protein that causes an increase in inositol trisphosphate which is rapidly metabolized, and which may release calcium from intracellular stores.

Demonstration of a functional motilin receptor in TE671 cells from human cerebellum.

BACKGROUND: Our laboratory has described the presence of motilin receptors in the rabbit cerebellum. We discovered its presence in the human TE671 cell line, which is of cerebellar origin. METHODS: Cytosolic Ca(2+) fluxes were monitored on a confocal microscope in cells loaded with Indo-1 and stimulated with motilin under various conditions. Binding studies were performed with 125I-[Nle(13)]porcine motilin. Using primers, PCR for the motilin receptor was performed. RESULTS: Cells responded to motilin after 45+/-20 s. At different concentrations of motilin (10(-8), 10(-7), 10(-6.5), 10(-6) and 10(-5) M) the percentage of responding cells was 0+/-0, 0.6+/-1.5, 4.9+/-4.7, 21.7+/-15 and 35.7+/-12, respectively. The response was blocked by the motilin antagonists [Phe(3), Nle(13)]po-motilin (0.8+/-1.8%) and GM-109 (0.0+/-0.0%) and mimicked by the agonist ABT-229 (23.6+/-15%). After stimulation with motilin, ABT-229 or [Phe(3),Leu(13)]po-motilin, but not with the antagonist GM-109, cells were desensitized. The response to motilin persisted in Ca(2+)-free solution (22.8+/-14.7%), was not affected by nifedipine (44+/-11%) but was abolished by incubation with thapsigargin (0+/-0%). Neither ryanodine, nor a previous stimulation with caffeine (0+/-0%) in Ca(2+)-free Krebs, nor both could block the response to motilin (28, 32.0+/-5.7, 41.3+/-6.1%, respectively). Binding studies revealed two binding sites for motilin, with a pK(d) of 8.9+/-0.05 and 6.11+/-0.61 (n=4). There were 100 times more low than high affinity receptors per cell. The presence of receptor mRNA was confirmed by PCR. CONCLUSION: Functional motilin receptors are present in TE671 cells. The response requires intracellular IP(3)-sensitive Ca(2+) stores. These cells may serve as a model of the central motilin receptor.