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Alimentary Pharmacology & Therapeutics May 2023Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different... (Review)
Review
BACKGROUND
Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different targets and modulate different physiological mechanisms.
AIMS
Address the questions: In gastroparesis, why should blocking one pathway causing vomiting, be more appropriate than another? Why might increasing gastric emptying via one mechanism be more appropriate than another?
METHODS
Drugs used clinically were identified via consensus opinions and reviews, excluding the poorly characterised. Their pharmacology was defined, mapped to mechanisms influencing vomiting and gastric emptying, and rationale developed for therapeutic use.
RESULTS
Vomiting: Rationale for 5-HT , D , H or muscarinic antagonists, and mirtazapine, amitriptyline, nortriptyline, are poor. Arguments for inhibiting central consequences of vagal afferent transmission by NK antagonism are complicated by doubts over effects on nausea. Gastric emptying: Confusion emerges because of side-effects of drugs increasing gastric emptying: Metoclopramide (5-HT agonist, D and 5-HT antagonist; also blocks some emetic stimuli and causes tardive dyskinesia) and Erythromycin (high-efficacy motilin agonist, requiring low doses to minimise side-effects). Limited trials with selective 5-HT agonists indicate variable efficacy.
CONCLUSIONS
Several drug classes inhibiting vomiting have no scientific rationale. NK antagonism has rationale but complicated by limited efficacy against nausea. Studies must resolve variable efficacy of selective 5-HT agonists and apparent superiority over motilin agonists. Overall, lack of robust activity indicates a need for novel approaches targeting nausea (e.g., modulating gastric pacemaker or vagal activity, use of receptor agonists or new targets such as GDF15) and objective assessments of nausea.
Topics: Humans; Gastroparesis; Gastric Emptying; Motilin; Serotonin; Vomiting; Nausea
PubMed: 36919196
DOI: 10.1111/apt.17466 -
The American Journal of the Medical... May 2018Gastric emptying (GE) of solids is delayed and autonomic dysfunction is detected in autoimmune gastritis (AIG). The goals of this study were to: (1) compare serum levels...
BACKGROUND
Gastric emptying (GE) of solids is delayed and autonomic dysfunction is detected in autoimmune gastritis (AIG). The goals of this study were to: (1) compare serum levels of ghrelin and motilin in subjects with delayed and normal GE and (2) investigate whether circulating antimyenteric antibodies (CAA), serum ghrelin levels and motilin levels have any effect on autonomic function.
MATERIALS AND METHODS
Noninvasive cardiovascular reflex tests were used in order to evaluate the autonomic function. GE was evaluated by a standard 2-hour scintigraphic test. Serum ghrelin and motilin levels were tested by enzyme-linked immunosorbent assay and CAA were tested by immunofluorescence.
RESULTS
The serum ghrelin and motilin levels in the patients with delayed GE (n = 22) were significantly decreased compared to the normal GE patients (n = 19), (67.55 ± 8.81 versus 126.79 ± 25.81pg/mL, P < 0.001 and 279.59 ± 111.12 versus 500.42 ± 155.95pg/mL, respectively, P < 0.001). Whereas, the serum ghrelin and motilin levels in the patients with deranged autonomic function (n = 26) were significantly decreased compared to the patients with normal autonomic function (n = 15), (80.73 ± 28.46 versus 127.79 ± 28.06pg/mL, P < 0.001 and 316.92 ± 160.47 versus 490.20 ± 141.02pg/mL, P < 0.001, respectively). None of the patients were positive for CAA.
CONCLUSIONS
Ghrelin and motilin levels in AIG subjects with delayed GE and deranged autonomic function were significantly decreased. The decrease in serum ghrelin and plasma motilin levels in AIG suggest their potential role in the delayed GE observed in these subjects.
Topics: Autoimmune Diseases; Autonomic Nervous System; Female; Gastric Emptying; Gastritis; Ghrelin; Humans; Male; Middle Aged; Motilin
PubMed: 29753372
DOI: 10.1016/j.amjms.2017.12.021 -
Combinatorial Chemistry & High... 2023The aim of the study was to explore the efficacy as well as the mechanism of action of Pitongshu (PTS) on rats with functional dyspepsia (FD) induced by iodoacetamide...
AIM
The aim of the study was to explore the efficacy as well as the mechanism of action of Pitongshu (PTS) on rats with functional dyspepsia (FD) induced by iodoacetamide gavage and tail clamping.
METHODS
The bioactive components of PTS were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), whereas the potential targets of PTS were obtained from the Similarity Ensemble Approach (SEA), TCMSP, and Swiss Target Prediction Database. The disease targets were obtained from the DisGeNET database, whereas Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the R Software. The method of iodoacetamide gavage combined with tail clamping was used to establish the FD rat model in this study. Body weight, food intake, gastrointestinal motility, gastric acidity and secretion, and the mechanical pain threshold of rats were measured. The open-field test was also performed. The stomach and duodenum were histologically observed. The levels of serotonin (5-HT), Calcitonin Gene-Related Peptide (CGRP), Motilin (MTL), and Gastrin (GAS) in gastric tissues were detected by ELISA.
RESULTS
A total of 139 bioactive components and 17 potential targets of PTS were identified through a network pharmacology approach. The results of GO and KEGG enrichment analyses indicated that PTS could reduce the 5-HT secretion of gastric tissues through the serotonergic synaptic pathway and alleviate the symptoms of FD, indicating that PTS plays a therapeutic role. The results of animal experiments showed that PTS could increase body weight and food intake, improve autonomous activity, and decrease gastric acidity and secretion in FD rats. Furthermore, gastric sensitivity increased in FD rats, and PTS treatment could significantly decrease it. The results of ELISA showed that the overexpression of 5-HT and CGRP was decreased after PTS treatment in FD rats. Lastly, PTS could significantly improve gastrointestinal motility, as well as the levels of GAS and MTL in FD rats.
CONCLUSION
PTS may reduce 5-HT secretion by regulating the serotonergic synaptic pathway, thereby reducing visceral sensitivity and alleviating the symptoms of FD.
Topics: Rats; Animals; Dyspepsia; Serotonin; Calcitonin Gene-Related Peptide; Iodoacetamide; Gastrointestinal Motility
PubMed: 36043772
DOI: 10.2174/1386207325666220827152654 -
Gut Feb 2016Hunger 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...
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 (β=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.
Topics: Appetite; Cholinesterase Inhibitors; Duodenum; Eating; Erythromycin; Gastrointestinal Motility; Ghrelin; Humans; Hunger; Manometry; Motilin; Muscle Contraction; Myoelectric Complex, Migrating; Neostigmine; Octreotide; Peptide Fragments; Somatostatin; Stomach
PubMed: 25539673
DOI: 10.1136/gutjnl-2014-308472 -
General and Comparative Endocrinology Jan 2021Ghrelin (GHRL) and motilin (MLN), gut peptides isolated from the mucosa of the stomach and duodenum, respectively, stimulate gastrointestinal (GI) motility in mammals...
Ghrelin (GHRL) and motilin (MLN), gut peptides isolated from the mucosa of the stomach and duodenum, respectively, stimulate gastrointestinal (GI) motility in mammals and birds. However, the functions of MLN and GHRL in amphibian GI tracts have not been examined in detail. To clarify the regulation of GI motility by the two peptides, the effects of human MLN and rat GHRL on contractility of isolated GI strips from three species of frogs, the black-spotted pond frog (pond frog; Pelophylax nigromaculata), bullfrog (Lithobates catesbeiana) and Western clawed frog (Xenopus; Xenopus tropicalis), were examined in in vitro experiments. The GI tract of each frog was divided into the stomach, upper intestine, middle intestine and lower intestine. Human MLN caused contractions of the stomach in the pond frog and upper intestine in the bullfrog and Xenopus, but other GI regions were insensitive to human MLN. Erythromycin did not cause contraction of the upper intestine of the bullfrog and Xenopus. Rat GHRL did not cause contraction of the stomach and small intestines in the pond frog and bullfrog, but it caused a concentration-dependent contraction in the stomach and upper intestine of Xenopus, while des-acyl rat GHRL did not cause any contraction of them. In conclusion, human MLN caused the contraction of the stomach or upper intestine in the three species of frogs, but GHRL was effective only in the stomach and upper intestine of Xenopus. On the basis of these data, MLN but not GHRL causes the GI region-dependent contractions in the frogs.
Topics: Animals; Anura; Gastrointestinal Motility; Gastrointestinal Tract; Ghrelin; Humans; In Vitro Techniques; Male; Motilin; Muscle Contraction; Rana catesbeiana; Rats; Xenopus
PubMed: 33153968
DOI: 10.1016/j.ygcen.2020.113649 -
Complementary Therapies in Medicine Jun 2024Acupuncture stands out as a prominent complementary and alternative medicine therapy employed for functional dyspepsia (FD). We conducted a Bayesian meta-analysis to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acupuncture stands out as a prominent complementary and alternative medicine therapy employed for functional dyspepsia (FD). We conducted a Bayesian meta-analysis to ascertain both the relative effectiveness and safety of various acupuncture methods in the treatment of functional dyspepsia.
METHODS
We systematically searched eight electronic databases, spanning from their inception to April 2023. The eligibility criteria included randomized controlled trials investigating acupuncture treatments for FD. Study appraisal was conducted using the Cochrane risk of bias tool. Pairwise and network meta-analyses were conducted using RevMan 5.3 and ADDIS V.1.16.6 software. Bayesian network meta-analysis was performed to compare and rank the efficacy of different acupuncture therapies for FD symptoms.
RESULTS
This study found that combining different acupuncture methods or using acupuncture in conjunction with Western medicine is more effective in improving symptoms of functional dyspepsia compared to using Western medicine alone. According to the comprehensive analysis results, notably, the combination of Western medicine and acupuncture exhibited superior efficacy in alleviating early satiation and postprandial fullness symptoms. For ameliorating epigastric pain, acupuncture combined with moxibustion proved to be the most effective treatment, while moxibustion emerged as the optimal choice for addressing burning sensations. Warming needle was identified as the preferred method for promoting motilin levels.
CONCLUSION
The findings of this study demonstrate that acupuncture, both independently and in conjunction with other modalities, emerged as a secure and effective treatment option for patients with functional dyspepsia.
Topics: Humans; Acupuncture Therapy; Bayes Theorem; Dyspepsia; Randomized Controlled Trials as Topic
PubMed: 38761869
DOI: 10.1016/j.ctim.2024.103051 -
Neoplasma 2017Gastrointestinal (GI) hormonal peptides play a role in the development of gastrointestinal malignancies, and their abnormal levels may contribute to dysmotility. The aim...
Gastrointestinal (GI) hormonal peptides play a role in the development of gastrointestinal malignancies, and their abnormal levels may contribute to dysmotility. The aim of this study was to analyze plasma concentrations of enterohormones (motilin, ghrelin, gastrin and pancreatic polypeptide) and to verify if their abnormal levels may contribute to the severity of dyspeptic symptoms in colorectal cancer patients. The study included 60 patients with colorectal malignancies (22 men and 38 women), among them 30 individuals with colon cancers (group A) and 30 subjects with rectal tumors (group B). Fasting plasma levels of pancreatic polypeptide (PP), motilin, gastrin and ghrelin were determined by means of ELISA. The results were compared with the respective parameters of healthy volunteers. Colon cancer patients presented with significantly lower concentrations of ghrelin than the subjects with rectal tumors and healthy controls (156.8±86.7 vs. 260.2±87.6 vs. 258.4±94.2 pg/ml, p=0.02), as well as with significantly higher levels of PP (265.5±66.3 vs. 154.1±54.6 vs. 148.3±64.3 pg/ml, p=0.005). Also the levels of motilin turned out to be lower in colon cancer patients than in the subjects with rectal malignancies and healthy controls. No statistically significant intergroups differences were found in plasma levels of gastrin (388.2±98.6 vs. 475.6±88.7 vs. 428.2±91.2 pg/ml, p>0.05). Epigastric bloating was the most frequent dyspeptic symptom, reported by 63.3% and 40% of patients with colon and rectal tumors, respectively. Our findings imply that colon cancer patients may present with abnormal plasma levels of enterohormones significantly more often than individuals with rectal malignancies. Dysmotility observed in colon cancer patients may result not only from anticancer surgery, but also from abnormal release of enterohormones, induced either by neoplastic process or by changes within the autonomic nervous system.
Topics: Case-Control Studies; Colorectal Neoplasms; Female; Gastrins; Ghrelin; Humans; Male; Motilin; Pancreatic Polypeptide
PubMed: 28253721
DOI: 10.4149/neo_2017_313 -
Life (Basel, Switzerland) Aug 2021Recent research has identified the gut-brain axis as a key mechanistic pathway and potential therapeutic target in depression. In this paper, the potential role of gut... (Review)
Review
Recent research has identified the gut-brain axis as a key mechanistic pathway and potential therapeutic target in depression. In this paper, the potential role of gut hormones as potential treatments or predictors of response in depression is examined, with specific reference to the peptide hormone motilin. This possibility is explored through two methods: (1) a conceptual review of the possible links between motilin and depression, including evidence from animal and human research as well as clinical trials, based on a literature search of three scientific databases, and (2) an analysis of the relationship between a functional polymorphism (rs2281820) of the motilin (MLN) gene and cross-national variations in the prevalence of depression based on allele frequency data after correction for potential confounders. It was observed that (1) there are several plausible mechanisms, including interactions with diet, monoamine, and neuroendocrine pathways, to suggest that motilin may be relevant to the pathophysiology and treatment of depression, and (2) there was a significant correlation between rs2281820 allele frequencies and the prevalence of depression after correcting for multiple confounding factors. These results suggest that further evaluation of the utility of motilin and related gut peptides as markers of antidepressant response is required and that these molecular pathways represent potential future mechanisms for antidepressant drug development.
PubMed: 34575041
DOI: 10.3390/life11090892 -
International Journal of Physiology,... 2023To explore the effect of Shenqi millet porridge on treating gastrointestinal function decline.
OBJECTIVE
To explore the effect of Shenqi millet porridge on treating gastrointestinal function decline.
METHODS
Clinical data of 72 patients with gastrointestinal function decline were retrospectively analyzed. Patients were divided into an observation group (n=36, treated with Shenqi millet porridge) and a control group (n=36, treated with Changweikang granule) according to the treatment methods. The therapeutic effect, quality of life, nutritional status, and levels of motilin and gastrin were analyzed.
RESULTS
The total response rate of the observation group was significantly higher than that of the control group (97.22% vs. 72.22%; P<0.05). Compared with the control group, the quality of life in the observation group was increased after treatment (all P<0.05), and the total protein and body mass index in the observation group were higher than those in the control group (all P<0.05), while the levels of motilin and gastrin in the observation group were lower than those in the control group (all P<0.05).
CONCLUSION
For patients with gastrointestinal function decline, the therapeutic regimen Shenqi millet porridge ameliorates the nutritional status of patients, as well as the quality of life and total therapeutic efficacy, also reduces the levels of motilin and gastrin. This regimen has high safety and clinical application value.
PubMed: 37216173
DOI: No ID Found -
Molecular Metabolism Dec 2021Motilin is a proximal small intestinal hormone with roles in gastrointestinal motility, gallbladder emptying, and hunger initiation. In vivo motilin release is...
OBJECTIVE
Motilin is a proximal small intestinal hormone with roles in gastrointestinal motility, gallbladder emptying, and hunger initiation. In vivo motilin release is stimulated by fats, bile, and duodenal acidification but the underlying molecular mechanisms of motilin secretion remain poorly understood. This study aimed to establish the key signaling pathways involved in the regulation of secretion from human motilin-expressing M-cells.
METHODS
Human duodenal organoids were CRISPR-Cas9 modified to express the fluorescent protein Venus or the Ca sensor GCaMP7s under control of the endogenous motilin promoter. This enabled the identification and purification of M-cells for bulk RNA sequencing, peptidomics, calcium imaging, and electrophysiology. Motilin secretion from 2D organoid-derived cultures was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), in parallel with other gut hormones.
RESULTS
Human duodenal M-cells synthesize active forms of motilin and acyl-ghrelin in organoid culture, and also co-express cholecystokinin (CCK). Activation of the bile acid receptor GPBAR1 stimulated a 3.4-fold increase in motilin secretion and increased action potential firing. Agonists of the long-chain fatty acid receptor FFA1 and monoacylglycerol receptor GPR119 stimulated secretion by 2.4-fold and 1.5-fold, respectively. Acidification (pH 5.0) was a potent stimulus of M-cell calcium elevation and electrical activity, an effect attributable to acid-sensing ion channels, and a modest inducer of motilin release.
CONCLUSIONS
This study presents the first in-depth transcriptomic and functional characterization of human duodenal motilin-expressing cells. We identify several receptors important for the postprandial and interdigestive regulation of motilin release.
Topics: Bile; Cells, Cultured; Duodenum; Fatty Acids, Nonesterified; Humans; Hydrogen-Ion Concentration; Motilin; Organoids
PubMed: 34662713
DOI: 10.1016/j.molmet.2021.101356