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.

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.

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 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.

Ghrelin and motilin in the gastrointestinal system.

Human ghrelin and human motilin, belonging to the ghrelin/motilin-related peptide family, share 36% amino acid sequence identity, while the human ghrelin receptor exhibits a remarkable 50% overall identity with the human motilin receptor. In addition to their structural resemblance, ghrelin and motilin are the only two mammalian hormones known to decrease in the postprandial period. Ghrelin and motilin participate in initiating the migrating motor complex in the stomach, and stimulate gastrointestinal motility, accelerate gastric emptying, and induce "gastric hunger". In addition to modulating the release of growth hormone and gut motility, ghrelin plays a crucial role in the secretion and protection of the stomach and colon. Ghrelin mimetics and motilin agonists are currently being developed to reverse gastrointestinal hypomotility disorders. With additional appetite-enhancing, adiposity-promoting, and anti-inflammatory effects, ghrelin and rikkunshito (a traditional Japanese herb enhancing acyl ghrelin signaling) are superior to motilin in the treatment of cancer-related anorexia and cachexia, post-chemotherapy symptoms, rheumatological diseases, age-related frailty, as well as post-operative, septic, and post-burn gut ileus.

Gastric emptying and symptoms of bulimia nervosa: effect of a prokinetic agent.

OBJECTIVE: Previous studies have suggested that delayed gastric emptying and abnormal postprandial release of hormones that influence satiation, particularly cholecystokinin (CCK), may play an important role in the pathophysiology of bulimia nervosa (BN). This study was designed to test these hypotheses as well as the efficacy of the prokinetic agent erythromycin in patients with BN. METHOD: Thirty-two normal-weight women with BN and 24 control participants consumed a large liquid test meal. Gastric emptying and pre- and postprandial release of CCK, peptide YY (PYY), and ghrelin were determined. Participants with BN were then recruited for double-blind treatment with erythromycin up to 500 mg three times daily vs. placebo for 6 weeks, following which they consumed a repeat test meal with gastric emptying and appetitive hormone measurements. RESULTS: CCK release at 15 min following the meal was marginally lower (p=0.1) in BN than in control participants. Rate of gastric emptying and postprandial hormone release were similar in BN and controls. BN patients assigned to erythromycin compared to those assigned to placebo had more rapid gastric emptying following treatment, but there were no differences in release of CCK, PYY, or ghrelin following the post-treatment test meal. Moreover, treatment with erythromycin was not associated with clinical response. DISCUSSION: The current study does not support the clinical utility of moderate dose erythromycin in treating BN. Furthermore, the findings suggest that a modest increase in gastric emptying rate is associated neither with altered postprandial hormonal release nor with clinical benefit in these patients. While providing no evidence for the effectiveness of prokinetic agents in this setting, our findings do not preclude the possibility that a greater increase in gastric emptying rate might prove beneficial.

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.

Efficacy of prophylactic oral erythromycin to improve enteral feeding tolerance in preterm infants: a randomised controlled study.

INTRODUCTION: Enteral feeding intolerance is a major problem in preterm infants. This study evaluated the safety and efficacy of prophylactic low-dose oral erythromycin, a motilin agonist, as a prokinetic agent in reducing the incidence of this problem. METHODS: From February to May 2008, a prospective randomised controlled trial was conducted at the Isfahan University of Medical Sciences, Isfahan, Iran. 70 uncomplicated preterm infants (28-34 weeks' gestation) weighing 1,000-1,500 g were randomly assigned to either a case group receiving low-dose oral erythromycin (6 mg/kg/day, in four doses over ten days) or a control group (n is 35 in each group) until they were fully fed enterally (150 ml/kg/day). Gavage feeding of the mother's milk was started within the first three days of life, and erythromycin was given simultaneously. The time taken to reach full enteral feeding and the total duration of feeding interruption due to intolerance were compared. RESULTS: The time taken to reach full enteral feeding was significantly shorter in the erythromycin group than the control group (10.11 +/- 2.51 versus 12.71 +/- 5.76 days, p is 0.01). In the control group, the mean duration of feeding interruption was significantly longer (84.00 +/- 62.58 versus 32.57 +/- 11.93 hours, p is 0.005) and more episodes of abdominal distention and significant gastric residue were also noted (p less than 0.05). No infant in the erythromycin group developed cardiac arrhythmias or pyloric stenosis. CONCLUSION: The prophylactic use of erythromycin may be warranted in very low birth weight infants, provided the efficacy and safety of the drug can be confirmed in further 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.

[Promotility drugs use in critical care: indications and limits?]. / Utilisation des médicaments prokinétiques en réanimation: indications et limites?

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.

Structure-activity relationships of 9-substituted-9-dihydroerythromycin-based motilin agonists: optimizing for potency and safety.

A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties.

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.

Prokinetic drugs for feed intolerance in critical illness: current and potential therapies.

Studies consistently show that nasogastric nutrition delivers only about 60% of nutritional goals in critically ill patients. The predominant reason is abnormal gastric motility, leading to delayed gastric emptying, which is evident clinically as large gastric residual volumes. Delayed gastric emptying occurs in about 50%-60% of critically ill patients who are fed enterally and can result in malnutrition. Furthermore, delayed gastric emptying may increase the risk of aspiration of gastric contents. Recent research has improved our understanding of the complex abnormalities of gastric motor function that underlie delayed gastric emptying in the critically ill. Feed intolerance can be treated with prokinetic drugs and/or by the placement of postpyloric feeding catheters. The place of prokinetic agents in the treatment of feed intolerance is as yet unclear, but current evidence supports the administration of erythromycin combined with metoclopramide as first-line therapy. Other novel drugs, such as methylnaltrexone, mitemcinal, ghrelin agonists and dexloxiglumide, have potential advantages over these agents but require further investigation before widespread clinical use.

Current treatment of nausea and vomiting associated with gastroparesis: antiemetics, prokinetics, tricyclics.

Gastroparesis is a symptomatic chronic disorder characterized by delayed gastric emptying without a mechanical obstruction. Gastroparesis is most often associated with diabetes, gastric surgery, and systemic disorders affecting the neuromuscular control of the stomach. However, no underlying etiology can be found in up to 40% of patients, a condition referred to as idiopathic gastroparesis. Due to the numerous potential etiologies and the highly variable clinical manifestations, the management of gastroparesis is particularly challenging. The purpose of this review is to provide an update on the use of antiemetics, prokinetics, and tricyclics for the treatment for nausea and vomiting associated with gastroparesis.

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.

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.

Expression of motilin in the hypothalamus and the effect of central erythromycin on gastric motility in diabetic rats.

OBJECTIVE: To investigate the expression of motilin-immunoreactive neurons in the hypothalamus and the effect of central administration of erythromycin (EM) on the regulation of gastric motility in diabetic rats. METHODS: The motilin immunoreactive neurons in the hypothalamus and the hippocampus were detected by immunohistochemistry with rabbit anti-motilin polyclonal antibody. To measure the gastric motility, force transducers were surgically affixed to the gastric serosa. A microinjection syringe was connected via a plastic tube to an injection cannula, which was connected with a stainless steel guide cannula. The syringe was inserted into the right lateral cerebral ventricle for microinjecting the chemicals. RESULTS: Diabetic mellitus was successfully induced in cohorts of rats. Motilin-immunoreactive neurons significantly increased in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus in the diabetic rats. Intracerebroventricular (i.c.v.) administration of EM, a motilin receptor agonist, stimulated the gastric motility of diabetic rats. EM (91.56 nmol, i.c.v.) dose-dependently increased the amplitude by (174.82 +/- 48.62)% (P<0.05), and increased the frequency by (70.43 +/- 27.11)% (P < 0.05) in 5 min. The stimulatory effect lasted more than 15 min to the end of the measurement, and can be blocked partially by the prior treatment of motilin receptor antagonist GM-109. CONCLUSION: Motilin-immunoreactive neurons are increased in the PVN and SON of the hypothalamus in diabetic rats. Centrally administered EM may regulate gastric motility by binding to the central motilin receptors, and central motilin might be involved in regulation of gastric motility in diabetic rats.

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.