Effect of Atilmotin, a Motilin Receptor Agonist, on Esophageal, Lower Esophageal Sphincter, and Gastric Pressures

Abstract

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 µg intravenously (IV), increases the early phase of gastric emptying. Prior studies at higher doses of 100–450 µg 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 µg). Another five subjects were studied at the highest dose (150 µg). Results Atilmotin at 150 µg 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 µg 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 µg 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 µg 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.

Regionally dependent neuromuscular functions of motilin and 5‐HT4 receptors in human isolated esophageal body and gastric fundus

“…The latter are consistent with previous studies using human fundus from both obese and cancer patients, together with a more potent and much larger ability of motilin to facilitate cholinergic function in human gastric antrum . These data are also consistent with the ability of atilmotin to reduce human distal esophageal contractions while at the same time increasing muscle tension in the LES and proximal regions of the stomach . Similarly, intravenously administered 13 Nle‐motilin has been shown to facilitate muscle tension and cholinergic activity in human LES .…”

“…Finally, it is important to ask why motilin (and the motilin peptide atilmotin) inhibit esophageal movements in the present studies whereas some clinical studies with erythromycin report stimulatory activity (but not all; see Introduction for references). This is a difficult question to answer but three possibilities require discussion.…”

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

“…To support the inclusion of 12 subjects, for analysis of the primary endpoint, pre‐existing data are only available on the absolute LOS pressure rather than the change from baseline. Korimilli and Parkman have previously reported a between subject standard deviation (SD) of 8.05 mmHg, which we corrected by multiplying the between subject variance by (0.3/0.7) to give an estimate of the within subject variance, to derive an estimate of the within subject SD of 5.27 mmHg . From these data, we decided that a clinically meaningful difference between camicinal and placebo would be a 8.7 mmHg increase in LOS pressure.…”

“…In addition to their prokinetic effects, marked controversy remains as to whether motilin agonists also have other physiological effect in the foregut . Therefore, the aim of this study was to evaluate the effect of camicinal on gastro‐physiological function.…”

Common Mechanism of Pathogenesis in Gastrointestinal Diseases Implied by Consistent Efficacy of Single Chinese Medicine Formula

“… 39 – 41 A manometric study has found that IBS patients exhibited significantly lower esophageal sphincter pressures compared with age and sex-matched controls. 39 Other researchers reveal a fluctuation among GI hormones, 42 glucose, 43 , 44 and oxidative free radicals 24 in patients with damages to the sphincters and smooth muscles. Interestingly, TCM formulae such as SNS exhibit consistent efficacy for maintaining the normal function of the sphincters, and thus may correct most, if not all, reflux-associated disorders.…”