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Shin A. Disorders of gastric motility. Lancet Gastroenterol Hepatol 2024; 9:1052-1064. [PMID: 39312926 DOI: 10.1016/s2468-1253(24)00231-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 07/08/2024] [Accepted: 07/15/2024] [Indexed: 09/25/2024]
Abstract
Gastroparesis is a disorder of delayed gastric emptying with associated symptoms of postprandial fullness, early satiety, nausea, vomiting, bloating, and abdominal pain. Functional dyspepsia is an upper gastrointestinal disorder of gut-brain interaction that presents with similar symptoms but is defined according to symptom patterns rather than gastric motor dysfunction. Although delayed gastric emptying is a defining feature of gastroparesis, other aspects of gastric neuromuscular dysfunction, such as gastric accommodation and visceral hypersensitivity might contribute to symptoms. Similarly, although functional dyspepsia is not defined by impaired gastric emptying, disordered gastric motility might underlie pathogenesis in some patients with functional dyspepsia. In the last decade, it has been increasingly recognised that these two disorders might represent varying presentations along a common continuum of neuromuscular dysfunction, although with differentiating features with respect to outcomes, diagnosis, and treatments. In this Review, an overview of gastroparesis and functional dyspepsia from the perspective of gastric motility is provided, discussing what is distinct and what is shared between these disorders.
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Affiliation(s)
- Andrea Shin
- Vatche and Tamar Manoukian Division of Digestive Diseases, G. Oppenheimer Center for Neurobiology of Stress and Resilience, Clinical Studies and Database Core, Goodman-Luskin Microbiome Center, David Geffen School of Medicine, University College Los Angeles, Los Angeles, CA, USA.
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Cho MS, Park JW, Kim J, Ko SJ. The influence of herbal medicine on serum motilin and its effect on human and animal model: a systematic review. Front Pharmacol 2023; 14:1286333. [PMID: 38161695 PMCID: PMC10755953 DOI: 10.3389/fphar.2023.1286333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 12/04/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction: Motilin (MLN) is a gastrointestinal (GI) hormone produced in the upper small intestine. Its most well understood function is to participate in Phase III of the migrating myoelectric complex component of GI motility. Changes in MLN availability are associated with GI diseases such as gastroesophageal reflux disease and functional dyspepsia. Furthermore, herbal medicines have been used for several years to treat various GI disorders. We systematically reviewed clinical and animal studies on how herbal medicine affects the modulation of MLN and subsequently brings the therapeutic effects mainly focused on GI function. Methods: We searched the PubMed, Embase, Cochrane, and Web of Science databases to collect all articles published until 30 July 2023, that reported the measurement of plasma MLN levels in human randomized controlled trials and in vivo herbal medicine studies. The collected characteristics of the articles included the name and ingredients of the herbal medicine, physiological and symptomatic changes after administering the herbal medicine, changes in plasma MLN levels, key findings, and mechanisms of action. The frequency patterns (FPs) of botanical drug use and their correlations were investigated using an FP growth algorithm. Results: Nine clinical studies with 1,308 participants and 20 animal studies were included in the final analyses. Herbal medicines in clinical studies have shown therapeutic effects in association with increased levels of MLN, including GI motility regulation and symptom improvement. Herbal medicines have also shown anti-stress, anti-tumor, and anti-inflammatory effects in vivo. Various biochemical markers may correlate with MLN levels. Markers may have a positive correlation with plasma MLN levels included ghrelin, acetylcholine, and secretin, whereas a negative correlation included triglycerides and prostaglandin E2. Markers, such as gastrin and somatostatin, did not show any correlation with plasma MLN levels. Based on the FP growth algorithm, Glycyrrhiza uralensis and Paeonia japonica were the most frequently used species. Conclusion: Herbal medicine may have therapeutic effects mainly on GI symptoms with involvement of MLN regulation and may be considered as an alternative option for the treatment of GI diseases. Further studies with more solid evidence are needed to confirm the efficacy and mechanisms of action of herbal medicines. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=443244, identifier CRD42023443244.
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Affiliation(s)
- Min-Seok Cho
- Department of Clinical Korean Medicine, Graduate School of Kyung Hee University, Seoul, Republic of Korea
| | - Jae-Woo Park
- Department of Internal Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jinsung Kim
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Seok-Jae Ko
- Department of Internal Korean Medicine, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
- Department of Gastroenterology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
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Fan Z, Qiu Y, Qi X, Xu J, Wan Y, Hao Y, Niu W, Huang J. Invasive acupuncture for gastroparesis after thoracic or abdominal surgery: a systematic review and meta-analysis. BMJ Open 2023; 13:e068559. [PMID: 37369406 PMCID: PMC10410841 DOI: 10.1136/bmjopen-2022-068559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
OBJECTIVES This meta-analysis aimed to systematically evaluate the efficacy of acupuncture in treating postsurgical gastroparesis syndrome (PGS) after thoracic or abdominal surgery. DESIGN Systematic review and meta-analysis. DATA SOURCES Twelve databases (PubMed, Embase, Cochrane Library Cochrane Central Register of Controlled Trials (CENTRAL), Medline (Ovid) (from 1946), Web of Science, EBSCO, Scopus, Open Grey, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Scientific Journals Database (VIP) and China Biology Medicine disc (CBM)) and three registration websites (WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and Chinese Clinical Trial Registry (ChiCTR)) were searched from the inception to September 2022, and citations of the included literature were screened. ELIGIBILITY CRITERIA All randomised controlled trials addressing invasive acupuncture for PGS. DATA EXTRACTION AND SYNTHESIS Key information on the included studies was extracted by two reviewers independently. Risk ratio (RR) with 95% CI was used for categorical data, and mean difference with 95% CI for continuous data. The quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. Outcomes were conducted with trial sequential analysis (TSA). RESULTS Fifteen studies with 759 patients met the inclusion criteria. Subgroup analyses revealed that compared with the drug group, the drug and acupuncture group had a greater positive effect on the total effective rate (TER) (nine trials, n=427; RR=1.20; 95% CI 1.08 to 1.32; P-heterogeneity=0.20, I2=28%, p=0.0004) and the recovery rate (RCR) (six trials, n = 294; RR = 1.61; 95% CI 1.30 to 1.98; P-heterogeneity=0.29, I2=19%, p<0.0001) of PGS after abdominal surgery. However, acupuncture showed no significant advantages in terms of the TER after thoracic surgery (one trial, p=0.13) or thoracic/abdominal surgery-related PGS (two trials, n = 115; RR=1.18; 95% CI 0.89 to 1.57; P-heterogeneity=0.08, I2=67%, p=0.24) and the RCR after thoracic/abdominal surgery (two trials, n=115; RR=1.40; 95% CI 0.97 to 2.01; P-heterogeneity=0.96, I2=0%, p=0.07). The quality of evidence for TER and RCR was moderate certainty. Only one study reported an acupuncture-related adverse event, in the form of mild local subcutaneous haemorrhage and pain that recovered spontaneously. TSA indicated that outcomes reached a necessary effect size except for clinical symptom score. CONCLUSION Based on subgroup analysis, compared with the drug treatment, acupuncture combined drug has significant advantages in the treatment of PGS associated with abdominal surgery, but not with thoracic surgery. PROSPERO REGISTRATION NUMBER CRD42022299189.
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Affiliation(s)
- Zhenjia Fan
- Department of minimally invasive acupuncture Oncology, Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yuqin Qiu
- Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuewei Qi
- Department of minimally invasive acupuncture Oncology, Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jingnan Xu
- Department of minimally invasive acupuncture Oncology, Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yuxiang Wan
- Department of minimally invasive acupuncture Oncology, Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yingxu Hao
- Oncology Department of Integrated Traditional Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Wenquan Niu
- Center for Evidence-Based Medicine, Capital Institute of Pediatrics, Beijing, China
| | - Jinchang Huang
- Department of minimally invasive acupuncture Oncology, Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, China
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Mori H, Verbeure W, Tanemoto R, Sosoranga ER, Jan Tack. Physiological functions and potential clinical applications of motilin. Peptides 2023; 160:170905. [PMID: 36436612 DOI: 10.1016/j.peptides.2022.170905] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 11/27/2022]
Abstract
Motilin is a gastrointestinal hormone secreted by the duodenum. This peptide regulates a characteristic gastrointestinal contraction pattern, called the migrating motor complex, during the fasting state. Motilin also affects the pressure of the lower esophageal sphincter, gastric motility and gastric accommodation in the gastrointestinal tract. Furthermore, motilin induces bile discharge into the duodenum by promoting gallbladder contraction, pepsin secretion in the stomach, pancreatic juice and insulin secretion from the pancreas. In recent years, it has been shown that motilin is associated with appetite, and clinical applications are expected for diseases affected by food intake, e.g. obesity, by regulating motilin levels. Gastric acid and bile are the two major physiological regulators for motilin release. Caloric foods have varying effects on motilin levels, depending on their composition. Among non-caloric foods, bitter substances reduce motilin levels and are therefore expected to have an appetite-suppressing effect. Various motilin receptor agonists and antagonists have been developed but have yet to reach clinical use.
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Affiliation(s)
- Hideki Mori
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Japan
| | - Wout Verbeure
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Rina Tanemoto
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | | | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
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Sato H, Grover M. Gastroparesis and Functional Dyspepsia: Spectrum of Gastroduodenal Neuromuscular Disorders or Unique Entities? GASTRO HEP ADVANCES 2023; 2:438-448. [PMID: 37151911 PMCID: PMC10162778 DOI: 10.1016/j.gastha.2022.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Gastroparesis is defined by delayed gastric emptying in the absence of mechanical obstruction of the stomach. Patients experience symptoms of nausea, vomiting, abdominal pain, fullness, and early satiety. The recognition of the disorder has progressed due to availability of gastric emptying scintigraphy and advancements made in understanding its pathophysiology and treatment options. The clinical presentation and treatment of gastroparesis overlap with a more commonly recognized disorder of gut-brain interaction, functional dyspepsia. Recent studies have reenergized the discussion whether these two are separate entities or perhaps reflect a spectrum of gastroduodenal neuromuscular disorders. The societal guidelines conflict on the utility of gastric emptying scintigraphy in assessment of patients with upper gastrointestinal symptoms. A better appraisal of similarities and differences between gastroparesis and functional dyspepsia will allow targeted treatment for these disorders. This is particularly important as specific pharmacological and endoscopic treatment options are being developed for gastroparesis which are unlikely to be helpful for functional dyspepsia. This review makes the case for considering these disorders in a spectrum where identification of both would most ideally position us toward providing the optimal clinical care.
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Affiliation(s)
- Hiroki Sato
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
- Division of Gastroenterology & Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Shah A, Kang S, Talley NJ, Do A, Walker MM, Shanahan ER, Koloski NA, Jones MP, Keely S, Morrison M, Holtmann GJ. The duodenal mucosa associated microbiome, visceral sensory function, immune activation and psychological comorbidities in functional gastrointestinal disorders with and without self-reported non-celiac wheat sensitivity. Gut Microbes 2022; 14:2132078. [PMID: 36303431 PMCID: PMC9621048 DOI: 10.1080/19490976.2022.2132078] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Frequently, patients with functional gastrointestinal disorders (FGIDs) report intolerance of wheat products. We compared gastrointestinal symptoms, sensory function, psychiatric comorbidities, gut-homing immune cells, and duodenal mucosa-associated microbiome (d-MAM) in FGID patients and controls with and without self-reported wheat sensitivity (SR-NCWS). We recruited 40 FGID patients and 20 controls referred by GPs for treatment. Gastrointestinal/extraintestinal symptoms, visceral sensory function, psychological comorbidities, and SR-NCWS were assessed in a standardized approach. Peripheral gut homing T-cells (CD4+α4+β7+CCR9+/CD8+α4+β7+CCR9+) were quantified, and the d-MAM was assessed by DNA sequencing for 46 subjects. Factors of bacterial genera were extracted utilizing factor analysis with varimax rotation and factors univariately associated with FGID or SR-NCWS included in a subsequent multivariate analysis of variance to identify statistically independent discriminators. Anxiety scores (p < .05) and increased symptom responses to a nutrient challenge (p < .05) were univariately associated with FGID. Gut homing T-cells were increased in FGID patients with SR-NCWS compared to other groups (p all <0.05). MANOVA revealed that anxiety (p = .03), visceral sensory function (p = 0.007), and a d-MAM factor comprise members of the Alloprevotella, Prevotella, Peptostreptococcus, Leptotrichia, and Veillonella lineages were significantly (p = .001) associated with FGID, while gut homing CD4+α4+ β7+CCR9+ T-cells were associated (p = .002) with SR-NCWS. Compared to controls, patients with and without SR-NCWS show that there are shifts in the amplicon sequence variants within specific bacterial genera between the FGID subgroups (particularly Prevotella and Streptococcus) as well as distinct bacterial taxa discriminatory for the two different FGID subtypes. Compared to controls, both FGID patients with and without SR-NCWS have an increased symptom response to a standardized nutrient challenge and increased anxiety scores. The FGID patients with SR-NCWS - as compared to FGID without SR-NCWS (and controls without SR-NCWS) - have increased gut homing T-cells. The d-MAM profiles suggest species and strain-based variations between the two FGID subtypes and in comparison to controls.
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Affiliation(s)
- Ayesha Shah
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia,Translational Research Institute Queensland, Australia,Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Seungha Kang
- Faculty of Medicine, University of Queensland, Brisbane, Australia,University of Queensland Diamantina Institute, Woolloongabba, Australia
| | - Nicholas J Talley
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, and Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Anh Do
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia,Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Marjorie M Walker
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, and Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Erin R Shanahan
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia,Translational Research Institute Queensland, Australia
| | - Natasha A Koloski
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia,Translational Research Institute Queensland, Australia,Faculty of Medicine, University of Queensland, Brisbane, Australia,College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, and Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Michael P Jones
- College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, and Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Simon Keely
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, and Hunter Medical Research Institute, New Lambton Heights, Australia
| | - Mark Morrison
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia,Faculty of Medicine, University of Queensland, Brisbane, Australia,University of Queensland Diamantina Institute, Woolloongabba, Australia,CONTACT Mark Morrison
| | - Gerald J Holtmann
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia,Translational Research Institute Queensland, Australia,Faculty of Medicine, University of Queensland, Brisbane, Australia,Gerald J Holtmann Princess Alexandra Hospital, Brisbane Department of Gastroenterology and Hepatology & University of Queensland 199 Ipswich Road, Woolloongabba, Queensland, Australia
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7
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Lazebnik LB, Golovanova EV, Volel BA, Korochanskaya NV, Lyalyukova EA, Mokshina MV, Mekhtiev SN, Mekhtieva OA, Metsaeva ZV, Petelin DS, Simanenkov VI, Sitkin SI, Cheremushkin SV, Chernogorova MV, Khavkin АI. Functional gastrointestinal disorders. Overlap syndrome Clinical guidelines of the Russian Scientific Medical Society of Internal Medicine and Gastroenterological Scientific Society of Russia. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:5-117. [DOI: 10.31146/1682-8658-ecg-192-8-5-117] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Affiliation(s)
- L. B. Lazebnik
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - E. V. Golovanova
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - B. A. Volel
- I. M. Sechenov First Moscow Medical State University
| | - N. V. Korochanskaya
- Federal State Budgetary Educational Institution of Higher Education “Kuban State Medical University” Health Ministry of Russian Federation; State Budgetary Institution of Health Care “Region Clinic Hospital Nr 2” Health Ministry of Krasnodar Region
| | - E. A. Lyalyukova
- FSBEI VO “Omsk State Medical University” of the Ministry of Health
| | - M. V. Mokshina
- Institute of therapy a. instrumental diagnostics of FSBEI VO “Pacifi c State Medical Unuversity”
| | | | | | - Z. V. Metsaeva
- Republican clinical hospital of Health Care Ministry of Northen Ossetia- Alania Republic
| | - D. S. Petelin
- I. M. Sechenov First Moscow Medical State University
| | - V. I. Simanenkov
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. I. Sitkin
- North- Western state medical University named after I. I. Mechnikov, Ministry of health of the Russian Federation
| | - S. V. Cheremushkin
- Federal State Budgetary Educational Institution of Higher Education “A. I. Yevdokimov Moscow State University of Medicine and Dentistry” of the Ministry of Healthcare of the Russion Federation
| | - M. V. Chernogorova
- Moscow regional research and clinical Institute of M. F. Vladimirsky; GBUZ MO “Podolsk City Clinical Hospital No. 3”
| | - А. I. Khavkin
- FSBAI HPE “N. I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation
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Meta-Analysis: Placebo Response and Its Determinants in Functional Dyspepsia. Am J Gastroenterol 2021; 116:2184-2196. [PMID: 34404084 DOI: 10.14309/ajg.0000000000001397] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Placebo response rates are relatively higher in clinical trials of disorders of brain-gut interaction. However, placebo response in functional dyspepsia (FD) has not been well described. Minimizing placebo response is important in drug development. We therefore conducted a meta-analysis to determine placebo response in trials for FD and to identify factors affecting placebo response rates. METHODS PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify double-blinded randomized controlled trials (RCTs) comparing medication with placebo in patients with FD. Both symptom improvement and complete relief were considered as separate primary endpoints in the analysis. Proportions of placebo patients experiencing any symptom improvement or complete relief were calculated. Dropouts after randomization for any reason were assumed to represent treatment failure for data extraction and analysis. Placebo response was pooled by a random-effects model, and effects of trial characteristics on the magnitude of placebo response were evaluated. RESULTS In 58 eligible placebo-controlled RCTs of FD from 52 selected citations, 6,732 of 17,890 participants in all trials received placebo. Pooled placebo response rates for symptom improvement and complete relief were 44.3% and 15.6%, respectively. The placebo response rate was lower when improvements were assessed for ≥8 weeks. Trials assessing complete symptom relief showed lower placebo response rates even in trials for <8 weeks. DISCUSSION Our systematic review and meta-analysis showed that pooled placebo response rates in double-blinded RCTs of FD depended on efficacy criteria. Trials assessing complete symptom relief showed stable low placebo response rates in short-term trials.
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9
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Wuestenberghs F, Gourcerol G. Editorial: on the road towards treatment of gastroparesis-accelerating but do we get closer? Aliment Pharmacol Ther 2021; 54:183-184. [PMID: 34170529 DOI: 10.1111/apt.16375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- Fabien Wuestenberghs
- Physiology Department, INSERM 1073-CIC/CRB 1404, CHU de Rouen, Normandy University, Rouen, France.,CHU UCL Namur, Department of Gastroenterology and Hepatology, Université catholique de Louvain, Yvoir, Belgium
| | - Guillaume Gourcerol
- Physiology Department, INSERM 1073-CIC/CRB 1404, CHU de Rouen, Normandy University, Rouen, France
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Van den Houte K, Scarpellini E, Verbeure W, Mori H, Schol J, Masuy I, Carbone F, Tack J. The Role of GI Peptides in Functional Dyspepsia and Gastroparesis: A Systematic Review. Front Psychiatry 2020; 11:172. [PMID: 32256403 PMCID: PMC7093580 DOI: 10.3389/fpsyt.2020.00172] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 02/21/2020] [Indexed: 12/12/2022] Open
Abstract
Functional dyspepsia (FD) and gastroparesis (GP) are common disorders of the upper gastrointestinal tract. The pathophysiology of these conditions is likely to be heterogenous, and factors such as altered motility, sensitivity and response to nutrition have been identified as putative underlying mechanisms. Motility, sensitivity as well as responses to nutrition can be influenced or mediated by peptide hormones and serotonin released from the gastrointestinal mucosa. This review summarizes the role of GI peptides in functional dyspepsia and gastroparesis. In most studies, the levels of somatostatin, ghrelin, and motilin did not differ between healthy volunteers and FD or GP patients, but higher symptom burden was often correlated with higher peptide levels. Ghrelin and motilin receptor agonists showed promising results in improvement of the gastric emptying, but the link with improvement of symptoms is less predictable. Serotonin agonists have a potential to improve symptoms in both FD and idiopathic gastroparesis. Drugs acting on the GLP-1 and on the PYY receptors deserve further investigation. There is a need for systematic large scale studies.
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Affiliation(s)
| | | | | | | | | | | | | | - Jan Tack
- Translational Research Center for Gastrointestinal Diseases, University of Leuven, Leuven, Belgium
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James J, Mair S, Doll W, Sandefer E, Wurtman D, Maurer A, Deane AM, Harris MS. The effects of ulimorelin, a ghrelin agonist, on liquid gastric emptying and colonic transit in humans. Neurogastroenterol Motil 2020; 32:e13784. [PMID: 32017341 DOI: 10.1111/nmo.13784] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 10/26/2019] [Accepted: 12/02/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Ulimorelin, a small molecule ghrelin agonist and prokinetic agent, was effective in animal models of gastroparesis and delayed transit. However, employing once daily administration, it failed in clinical trials of postoperative ileus (POI), a condition in which colonic motility recovers last. The aim of this study was to evaluate drug dosing and regional differences in drug activity between stomach and colon. METHODS Gastric emptying was assessed by scintigraphy in healthy adults at single doses of 600-1200 µg kg-1 and multiple doses of 80-600 µg kg-1 Q8H for 7 days. Colonic motility was assessed by 7-region scintigraphic analysis at a dose of 600 µg kg-1 for 2 days. The primary endpoints were percent change in time to 50% (∆t50 ) liquid gastric emptying on Days 1, 4, and 6 and the geometric mean center of colonic transit at 24 hours (GC24 ). Plasma concentrations of free and total ulimorelin were measured for pharmacokinetic and exposure-response modeling. KEY RESULTS Ulimorelin 150-600 µg kg-1 every 8 hours resulted in statistically significant improvements (∆t50 = 23% to 46% (P < .05)) in gastric emptying from baseline that were sustained through Day 6. However, no effects on GC24 were observed. Pharmacokinetic analyses suggested that the free concentrations of ulimorelin achieved in POI trials and dosing frequency may have been inadequate. CONCLUSIONS AND INFERENCES Ulimorelin is a potent gastric prokinetic but lacks evidence of activity in the human colon, pointing to the stomach as the predominant site of action of ghrelin in humans; ClinicalTrials.gov NCT02993055.
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Affiliation(s)
- Joyce James
- Lyric Pharmaceuticals, Inc., South San Francisco, CA, USA
| | | | | | | | - David Wurtman
- Lyric Pharmaceuticals, Inc., South San Francisco, CA, USA
| | - Alan Maurer
- Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Adam M Deane
- Intensive Care Unit, Royal Melbourne Hospital, University of Melbourne, Melbourne, Vic., Australia
| | - M Scott Harris
- Lyric Pharmaceuticals, Inc., South San Francisco, CA, USA
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12
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Ducrotte P, Coffin B, Bonaz B, Fontaine S, Bruley Des Varannes S, Zerbib F, Caiazzo R, Grimaud JC, Mion F, Hadjadj S, Valensi PE, Vuitton L, Charpentier G, Ropert A, Altwegg R, Pouderoux P, Dorval E, Dapoigny M, Duboc H, Benhamou PY, Schmidt A, Donnadieu N, Gourcerol G, Guerci B. Gastric Electrical Stimulation Reduces Refractory Vomiting in a Randomized Crossover Trial. Gastroenterology 2020; 158:506-514.e2. [PMID: 31647902 DOI: 10.1053/j.gastro.2019.10.018] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 09/10/2019] [Accepted: 10/01/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS There have been conflicting results from trials of gastric electrical stimulation (GES) for treatment of refractory vomiting, associated or not with gastroparesis. We performed a large, multicenter, randomized, double-blind trial with crossover to study the efficacy of GES in patients with refractory vomiting, with or without gastroparesis. METHODS For 4 months, we assessed symptoms in 172 patients (66% women; mean age ± standard deviation, 45 ± 12 years; 133 with gastroparesis) with chronic (>12 months) of refractory vomiting (idiopathic, associated with a type 1 or 2 diabetes, or postsurgical). A GES device was implanted and left unactivated until patients were randomly assigned, in a double-blind manner, to groups that received 4 months of stimulation parameters (14 Hz, 5 mA, pulses of 330 μs) or no stimulation (control); 149 patients then crossed over to the other group for 4 months. Patients were examined at the end of each 4-month period (at 5 and 9 months after implantation). Primary endpoints were vomiting score, ranging from 0 (daily vomiting) to 4 (no vomiting), and the quality of life, assessed by the Gastrointestinal Quality of Life Index scoring system. Secondary endpoints were changes in other digestive symptoms, nutritional status, gastric emptying, and control of diabetes. RESULTS During both phases of the crossover study, vomiting scores were higher in the group with the device on (median score, 2) than the control group (median score, 1; P < .001), in diabetic and nondiabetic patients. Vomiting scores increased significantly when the device was ON in patients with delayed (P < .01) or normal gastric emptying (P = .05). Gastric emptying was not accelerated during the ON period compared with the OFF period. Having the GES turned on was not associated with increased quality of life. CONCLUSIONS In a randomized crossover study, we found that GES reduced the frequency of refractory vomiting in patients with and without diabetes, although it did not accelerate gastric emptying or increase of quality of life. Clinicaltrials.gov, Number: NCT00903799.
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Affiliation(s)
- Philippe Ducrotte
- Rouen University Hospital-Inserm UMR 1073/Inserm CIC-CRB 1404, Rouen, France
| | | | - Bruno Bonaz
- Grenoble University Hospital, Grenoble, France
| | | | | | - Frank Zerbib
- Department of Gastroenterology, Hepatology, and Digestive Oncology, Bordeaux University Hospital, Bordeaux, France
| | | | | | | | | | | | | | | | | | - Romain Altwegg
- Montpellier University Hospital-Lapeyronie, Montpellier, France
| | | | | | - Michel Dapoigny
- Clermont-Ferrand University Hospital, Clermont Ferrand, France
| | - Henri Duboc
- Paris-HP Louis Mourier Hospital, Colombes, France
| | | | | | - Nathalie Donnadieu
- Rouen University Hospital-Inserm UMR 1073/Inserm CIC-CRB 1404, Rouen, France
| | - Guillaume Gourcerol
- Rouen University Hospital-Inserm UMR 1073/Inserm CIC-CRB 1404, Rouen, France.
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Grover M, Farrugia G, Stanghellini V. Gastroparesis: a turning point in understanding and treatment. Gut 2019; 68:2238-2250. [PMID: 31563877 PMCID: PMC6874806 DOI: 10.1136/gutjnl-2019-318712] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/29/2019] [Accepted: 08/22/2019] [Indexed: 12/21/2022]
Abstract
Gastroparesis is defined by delayed gastric emptying (GE) and symptoms of nausea, vomiting, bloating, postprandial fullness, early satiety and abdominal pain. Most common aetiologies include diabetes, postsurgical and postinfectious, but in many cases it is idiopathic. Clinical presentation and natural history vary by the aetiology. There is significant morbidity and healthcare utilisation associated with gastroparesis. Mechanistic studies from diabetic animal models of delayed GE as well as human full-thickness biopsies have significantly advanced our understanding of this disorder. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system through paracrine and oxidative stress mediators is likely central to the pathogenesis of gastroparesis. Scintigraphy and 13C breath testing provide the most validated assessment of GE. The stagnant gastroparesis therapeutic landscape is likely to soon see significant changes. Relatively newer treatment strategies include antiemetics (aprepitant), prokinetics (prucalopride, relamorelin) and fundic relaxants (acotiamide, buspirone). Endoscopic pyloromyotomy appears promising over the short term, especially for symptoms of nausea and vomiting. Further controlled trials and identification of the appropriate subgroup with pyloric dysfunction and assessment of long-term outcomes are essential. This review highlights the clinical presentation, diagnosis, mechanisms and treatment advancements for gastroparesis.
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Affiliation(s)
- Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vincenzo Stanghellini
- Department of Digestive Diseases and Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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14
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Wuestenberghs F, Juge M, Melchior C, Desprez C, Leroi AM, Gourcerol G. Association Between Symptoms, Quality of Life, and Gastric Emptying in Dyspeptic Patients. J Neurogastroenterol Motil 2019; 25:534-543. [PMID: 31587545 PMCID: PMC6786450 DOI: 10.5056/jnm19060] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/25/2019] [Accepted: 07/20/2019] [Indexed: 12/17/2022] Open
Abstract
Background/Aims Association between symptoms, quality of life and gastric emptying in dyspepsia is inconsistent in the literature. The aim of our study is to investigate if gastric emptying is associated with specific symptoms and quality of life in dyspeptic patients. Methods We reviewed retrospectively gastric emptying measured by 13C-labelled octanoate breath testing for more than 6 hours in 198 consecutive patients with dyspepsia complaints. Gastrointestinal symptoms were assessed using a 5-points Likert scale and by a symptomatic composite score, whereas quality of life was measured by the GIQLI. Results In our cohort, 90 patients (45%) had a delayed gastric emptying (half emptying time above 166 minutes when assessed over 6–8 hours). There was no difference in symptoms or quality of life between patients with or without delayed gastric emptying. However, patients with severely delayed gastric emptying (half emptying time above 200 minutes) had increased postprandial fullness (P = 0.012), abdominal pain (P = 0.026), bloating (P = 0.044), early satiety (P = 0.018), symptomatic composite score (P = 0.005), and a lower quality of life (P = 0.018). This association was no longer observed if the calculation of gastric emptying was limited to the first 4-hour samples. Conclusions There is no association between symptoms, quality of life and gastric emptying in an overall dyspeptic population. However, there is an association between symptoms, quality of life of delayed gastric emptying in the subgroup of patients with severely delayed gastric emptying. An 8-hour measurement of gastric emptying should be recommended.
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Affiliation(s)
- Fabien Wuestenberghs
- Department of Gastroenterology and Hepatology, CHU UCL Namur, Godinne University Hospital, UCLouvain, Yvoir, Belgium.,Department of Physiology, Rouen University Hospital, Normandie University, Rouen, France.,Nutrition, Gut and Brain Laboratory (INSERM UMR 1073), Institute for Biomedical Research and innovation, Rouen University, Normandie University, Rouen, France
| | - Mathilde Juge
- Department of Gastroenterology, Rouen University Hospital, Normandie University, Rouen, France
| | - Chloé Melchior
- Nutrition, Gut and Brain Laboratory (INSERM UMR 1073), Institute for Biomedical Research and innovation, Rouen University, Normandie University, Rouen, France.,Department of Gastroenterology, Rouen University Hospital, Normandie University, Rouen, France
| | - Charlotte Desprez
- Department of Physiology, Rouen University Hospital, Normandie University, Rouen, France
| | - Anne-Marie Leroi
- Department of Physiology, INSERM CIC-CRB 1404, Rouen University Hospital, INSERM Unit 1073, UNIROUEN, Normandie University, Rouen France
| | - Guillaume Gourcerol
- Department of Physiology, Rouen University Hospital, Normandie University, Rouen, France.,Nutrition, Gut and Brain Laboratory (INSERM UMR 1073), Institute for Biomedical Research and innovation, Rouen University, Normandie University, Rouen, France
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15
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Deloose E, Verbeure W, Depoortere I, Tack J. Motilin: from gastric motility stimulation to hunger signalling. Nat Rev Endocrinol 2019; 15:238-250. [PMID: 30675023 DOI: 10.1038/s41574-019-0155-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
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.
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Affiliation(s)
- Eveline Deloose
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Wout Verbeure
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Inge Depoortere
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.
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16
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Prokinetics for Functional Dyspepsia: A Systematic Review and Meta-Analysis of Randomized Control Trials. Am J Gastroenterol 2019; 114:233-243. [PMID: 30337705 DOI: 10.1038/s41395-018-0258-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVES Prokinetics are recommended for the treatment of functional dyspepsia (FD) but systematic reviews give conflicting results on the efficacy of these agents. We have therefore conducted an updated systematic review to support the 2017 joint ACG/CAG dyspepsia guidelines. METHODS Electronic databases, including MEDLINE, EMBASE, and CENTRAL, were searched until September 2017 for randomized controlled trials (RCTs) comparing either prokinetics and placebo or two types of prokinetics to improve FD symptoms. The primary outcome was absence or improvement of dyspeptic symptoms at the end of treatment. Double-blind eligibility assessment and data extraction was performed. Pooled risk ratios of symptoms persisting or adverse events occurring, and standardized mean difference of quality-of-life (QoL) scores with 95% CI, using a random effects model, were calculated. Quality of evidence was assessed using GRADE. RESULTS The search identified 1388 citations; 38 studies in 35 papers were included. Of these, 29 trials comparing prokinetics with placebo were found. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR 0.81, 95% CI 0.74 to 0.89; I2 91%; NNT 7), regardless of FD subtype or ethnicity. When comparing two types of prokinetic, the most commonly used comparator was domperidone. There was no difference in reducing global symptoms (RR 0.94, 95% CI 0.83 to 1.07). QoL was not improved with prokinetic treatment. The adverse events with individual prokinetics were not different from placebo, except for cisapride. The GRADE assessment rated the quality of the evidence in each outcome as very low. CONCLUSIONS From the current evidence, prokinetics may be effective for the treatment in all subtypes of FD, with very low quality of evidence. There was no difference between prokinetics for dyspeptic symptom improvement. High-quality RCTs with large sample sizes of FD patients are needed to verify the efficacy of prokinetics.
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Pittayanon R, Yuan Y, Bollegala NP, Khanna R, Leontiadis GI, Moayyedi P, Cochrane Upper GI and Pancreatic Diseases Group. Prokinetics for functional dyspepsia. Cochrane Database Syst Rev 2018; 10:CD009431. [PMID: 30335201 PMCID: PMC6516965 DOI: 10.1002/14651858.cd009431.pub3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Dyspepsia is a common condition associated with gastrointestinal (GI) disease. Prokinetics are the treatment of choice for functional dyspepsia (FD). However, the role of prokinetics in FD treatment is still controversial. OBJECTIVES We conducted a systematic review and meta-analysis of randomised control trials (RCTs) examining the efficacy of prokinetics in the treatment of FD. The primary outcome was overall absence of or improvement of symptoms and symptom scores at the end of treatment. We also evaluated quality of life (QoL) and adverse events as secondary outcomes. SEARCH METHODS We performed a systematic search of MEDLINE, Embase, the Cochrane Library, and CINAHL, from 1946 until September 2017. RevMan 5.3 was used to calculate pooled risk ratios (RR) of symptoms persisting or without improved QoL or adverse events, mean difference (MD) or standardised mean difference (SMD) of post-treatment symptoms scores, changes of symptom scores, and QoL, when appropriate with 95% confidence intervals (CI), using a random-effects model. Quality of evidence was evaluated using GRADE methodology. SELECTION CRITERIA We included studies that were parallel group RCTs comparing one prokinetic with either placebo or another prokinetic of the same or different class for the treatment of FD. Studies involved adults who presented with dyspepsia symptoms and who had negative or insignificant findings on endoscopy as well as no other organic and metabolic disorders. Studies only including participants with primarily reflux or heartburn symptoms were excluded. DATA COLLECTION AND ANALYSIS Two review authors independently assessed study eligibility, study quality and performed data extraction. MAIN RESULTS From an initial 1388 citations, we identified 43 studies in 40 papers. Of those, 29 studies with 10,044 participants compared six prokinetics with placebo for the outcome of absence of symptoms or symptom improvement. There was a statistically significant effect of prokinetic treatment in reducing global symptoms of FD (RR of remaining dyspeptic = 0.81, 95% CI 0.74 to 0.89; number needed to treat for an additional beneficial outcome (NNTB) =7, very low-quality evidence) with considerable heterogeneity; I2 = 91% (P < 0.00001). After removing cisapride from the analysis, the effect of prokinetics in global symptom improvement still persisted, compared to placebo (RR 0.87, 95% CI 0.80 to 0.94), but was still based on very low-quality evidence. The result showed persistence of significant improvement in subgroups of studies at unclear or at low risk of bias (RR 0.86, 95% CI 0.80-0.92), and in subgroups by molecules of cisapride (RR 0.71, 95% CI 0.54 to 0.93; NNTB = 4), acotiamide (RR 0.94, 95% CI 0.91 to 0.98; NNTB = 20) and tegaserod(RR 0.89, 95% CI 0.82 to 0.96; NNTB = 14).Ten studies compared different types of prokinetics with each other and the most commonly used comparator was domperidone, 10 mg three times a day (eight of the 10 studies). There was a significantly better post-treatment symptom score in other prokinetics, compared to domperidone (SMD -0.19, 95% CI -0.35 to -0.03, very low-quality evidence), but no difference in reducing global symptom (RR 0.94, 95% CI 0.83 to 1.07), and mean difference symptom scores (SMD -0.13, 95% CI -0.31 to 0.05). We found five studies that assessed quality of life, but there was no benefit in improving quality of life with prokinetic treatment (SMD 0.11, 95% CI -0.10 to 0.33; participants = 1774). The adverse events in individual prokinetics was not different from placebo (RR 1.09, 95% CI 0.95 to 1.25; participants = 3811; studies = 17). However, when we looked at the adverse effects by each prokinetic, there were overall greater adverse effects in the active treatment group with cisapride (RR 1.31, 95% CI 1.03 to 1.65; P = 0.03). The most common side effects were diarrhoea, abdominal discomfort and nausea. The funnel plot was asymmetric (Egger's test, P = 0.02) implying reporting bias or other small-study effects may be, in part, driving the benefit of prokinetics compared to placebo in this meta-analysis. The GRADE assessment of the quality of the evidence in each outcome are mostly low or very low due to concerns around risk of bias in study design, unexplained heterogeneity and possible publication bias. AUTHORS' CONCLUSIONS Due to low, or very low, quality of evidence, we are unable to say whether prokinetics are effective for the treatment of functional dyspepsia . We are uncertain which of the individual prokinetic drugs is the most effective as well as whether prokinetics can improve quality of life. Apart from cisapride, prokinetics are well-tolerated. Good quality RCTs are needed to verify the efficacy of prokinetics.
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Affiliation(s)
- Rapat Pittayanon
- McMaster UniversityDepartment of Medicine, Division of GastroenterologyHamiltonONCanada
- Chulalongkorn University and King Chulalongkorn Memorial Hospital The Thai Red CrossDivision of Gastroenterology, Department of Medicine, Faculty of Medicine1873 Rama 4 RoadPatumwanBangkokThailand10330
| | - Yuhong Yuan
- McMaster UniversityDepartment of Medicine, Division of GastroenterologyHamiltonONCanada
| | | | - Reena Khanna
- University of Western OntarioDepartment of MedicineLondonONCanada
| | | | - Paul Moayyedi
- McMaster UniversityDepartment of Medicine, Division of GastroenterologyHamiltonONCanada
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Tack J, Corsetti M, Camilleri M, Quigley EM, Simren M, Suzuki H, Talley NJ, Tornblom H, Van Oudenhove L. Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts. Gut 2018; 67:1425-1433. [PMID: 28814481 DOI: 10.1136/gutjnl-2016-312230] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 06/07/2017] [Accepted: 06/09/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances. METHODS A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs. RESULTS Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism. CONCLUSION Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies.
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Affiliation(s)
- Jan Tack
- Translational Research Center for Gastrointestinal Disorders, KULeuven, Leuven, Belgium
| | - Maura Corsetti
- Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Michael Camilleri
- CENTER Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Eamonn Mm Quigley
- Division of Gastroenterology and Hepatology, Lynda K and David M Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, Texas, USA
| | - Magnus Simren
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Nicholas J Talley
- Faculty of Health, University of Newcastle, Callaghan, New South Wales, Australia
| | - Hans Tornblom
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lukas Van Oudenhove
- Translational Research Center for Gastrointestinal Disorders, KULeuven, Leuven, Belgium
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Fukui H, Xu X, Miwa H. Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders. J Neurogastroenterol Motil 2018; 24:367-386. [PMID: 29969855 PMCID: PMC6034676 DOI: 10.5056/jnm18071] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 05/21/2018] [Indexed: 12/13/2022] Open
Abstract
Gut microbiota exert a pivotal influence on various functions including gastrointestinal (GI) motility, metabolism, nutrition, immunity, and the neuroendocrine system in the host. These effects are mediated by not only short-chain fatty acids produced by microbiota but also gut hormones and inflammatory signaling by enteroendocrine and immune cells under the influence of the microbiota. GI motility is orchestrated by the enteric nervous system and hormonal networks, and disturbance of GI motility plays an important role in the pathophysiology of functional gastrointestinal disorders (FGIDs). In this context, microbiota-associated mediators are considered to act on specific receptors, thus affecting the enteric nervous system and, subsequently, GI motility. Thus, the pathophysiology of FGIDs is based on alterations of the gut microbiota/gut hormone axis, which have crucial effects on GI motility.
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Affiliation(s)
- Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
| | - Xin Xu
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
- Department of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin,
China
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
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20
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Liu N, Abell T. Gastroparesis Updates on Pathogenesis and Management. Gut Liver 2018; 11:579-589. [PMID: 28535580 PMCID: PMC5593319 DOI: 10.5009/gnl16336] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 09/09/2017] [Indexed: 12/11/2022] Open
Abstract
Gastroparesis (Gp) is a chronic disease that presents with clinical symptoms of early satiety, bloating, nausea, vomiting, and abdominal pain. Along with these symptoms, an objective finding of delayed gastric emptying, along with a documented absence of gastric outlet obstruction, are required for diagnosis. This article focuses on updates in the pathogenesis and management of Gp. Recent studies on full thickness biopsies of Gp patients have shed light on the complex interactions of the central, autonomic, and enteric nervous systems, which all play key roles in maintaining normal gut motility. The management of Gp has evolved beyond prokinetics and antiemetics with the use of gastric electrical stimulators (GES). In addition, this review aims to introduce the concept of gastroparesis-like syndrome (GLS). GLS helps groups of patients who have the cardinal symptoms of Gp but have a normal or rapid emptying test. Recent tests have shown that patients with Gp and GLS have similar pathophysiology, benefit greatly from GES placement, and likely should be treated in a similar manner.
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Affiliation(s)
- Nanlong Liu
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY, USA
| | - Thomas Abell
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY, USA
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21
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Tseng AS, Crowell MD, DiBaise JK. Clinical utility of gastric emptying scintigraphy: Patient and physician perspectives. Neurogastroenterol Motil 2018; 30:e13279. [PMID: 29266606 DOI: 10.1111/nmo.13279] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 12/04/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND The use of gastric emptying scintigraphy (GES) in the evaluation of patients with dyspeptic symptoms is controversial. Our aim was to investigate objective and subjective parameters of clinical utility of GES from the perspectives of both the patient and the ordering physician. METHODS Socio-demographic features, healthcare resource utilization, gastroparetic symptoms and quality of life (QoL) were obtained from consecutive patients referred for GES immediately prior to GES and again 4 months later. The ordering physician received a brief survey 2 weeks after the GES regarding their perceptions on whether the test provided them with clinically useful information. KEY RESULTS One hundred and seventy-two (mean age ± SD 52.0 ± 17.9; 78% female) of 266 patients enrolled completed both the baseline and follow-up questionnaires and comprised our study population. At baseline, patients with abnormal GES had significantly higher gastroparesis symptom scores and reduced QoL. At the 4-month follow-up, an improvement in symptoms and QoL was seen, but the degree of improvement was not significantly different between those with a normal or abnormal GES. One hundred and ninety-seven ordering physicians completed the survey and perceived that GES, particularly when abnormal, provided new information (91%) and resulted in a change in diagnosis (58%) and management (60%). CONCLUSIONS & INFERENCES Although patients with an abnormal GES generally had worse symptoms and lower QoL, the results of GES did not help to identify those with improved or worsened symptoms or QoL at follow-up. Nevertheless, the ordering physicians generally felt that the results of GES were helpful in managing these patients.
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Affiliation(s)
- A S Tseng
- Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA
| | - M D Crowell
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - J K DiBaise
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
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22
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Lacy BE, Saito YA, Camilleri M, Bouras E, DiBaise JK, Herrick LM, Szarka LA, Tilkes K, Zinsmeister AR, Talley NJ. Effects of Antidepressants on Gastric Function in Patients with Functional Dyspepsia. Am J Gastroenterol 2018; 113:216-224. [PMID: 29257140 DOI: 10.1038/ajg.2017.458] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Accepted: 10/09/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood. AIMS Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology. METHODS This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS). RESULTS In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS-PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02). CONCLUSIONS Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study.
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Affiliation(s)
- B E Lacy
- Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Y A Saito
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - M Camilleri
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - E Bouras
- Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - J K DiBaise
- Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - L M Herrick
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - L A Szarka
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - K Tilkes
- Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - A R Zinsmeister
- Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - N J Talley
- Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia
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Deloose E, Depoortere I, de Hoon J, Van Hecken A, Dewit OE, Vasist Johnson LS, Barton ME, Dukes GE, Tack J. Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans. Neurogastroenterol Motil 2018; 30. [PMID: 28782145 DOI: 10.1111/nmo.13173] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 06/30/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. METHODS In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.
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Affiliation(s)
- E Deloose
- KU Leuven (University of Leuven), TARGID, Leuven, Belgium
| | - I Depoortere
- KU Leuven (University of Leuven), TARGID, Leuven, Belgium
| | - J de Hoon
- KU Leuven (University of Leuven), Center for Clinical Pharmacology, Leuven, Belgium
| | - A Van Hecken
- KU Leuven (University of Leuven), Center for Clinical Pharmacology, Leuven, Belgium
| | - O E Dewit
- GSK Research and Development, GSK, Cambridge, UK
| | | | - M E Barton
- GSK Research and Development, GSK, Research Triangle Park, NC, USA
| | - G E Dukes
- GSK Research and Development, GSK, Research Triangle Park, NC, USA
| | - J Tack
- KU Leuven (University of Leuven), TARGID, Leuven, Belgium
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Navas CM, Patel NK, Lacy BE. Gastroparesis: Medical and Therapeutic Advances. Dig Dis Sci 2017; 62:2231-2240. [PMID: 28721575 DOI: 10.1007/s10620-017-4679-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 07/10/2017] [Indexed: 02/08/2023]
Abstract
Gastroparesis is a chronic, bothersome, and often disabling neuromuscular disorder of the upper gastrointestinal tract. The most frequently reported symptoms of gastroparesis include nausea, vomiting, epigastric pain, early satiety, and unintentional weight loss. Etiologies of gastroparesis include diabetes, connective tissue disorders, prior infection, mesenteric ischemia, and post-surgical complications. The largest category of gastroparesis patients is comprised of those in whom no definitive cause can be identified (idiopathic gastroparesis). The individual and societal burden of gastroparesis is substantial. It considerably reduces patients' quality of life accompanied by a significant negative impact to the healthcare system. The current treatments of gastroparesis are less than ideal. Dietary modification may improve symptoms in patients with mild disease. Metoclopramide is the only medication currently approved for the treatment of gastroparesis; however, it is associated with adverse effects in a sizable proportion of patients. Other medications are frequently employed to treat symptoms of nausea and vomiting, although technically all are used off-label since they are not FDA approved for the treatment of gastroparesis. These data highlight the need to identify novel, more effective treatment options for this disabling disease. This review will provide a brief synopsis on the epidemiology, etiology, and impact of gastroparesis, discussing new therapeutic advances.
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Affiliation(s)
- Christopher M Navas
- Division of Gastroenterology and Hepatology, 1 Medical Center Drive, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA.
| | - Nihal K Patel
- Division of Gastroenterology and Hepatology, 1 Medical Center Drive, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA
| | - Brian E Lacy
- Division of Gastroenterology and Hepatology, 1 Medical Center Drive, Dartmouth-Hitchcock Medical Center, Lebanon, NH, 03756, USA
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25
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Moayyedi P, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N. ACG and CAG Clinical Guideline: Management of Dyspepsia. Am J Gastroenterol 2017. [PMID: 28631728 DOI: 10.1038/ajg.2017.154] [Citation(s) in RCA: 365] [Impact Index Per Article: 45.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
We have updated both the American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG) guidelines on dyspepsia in a joint ACG/CAG dyspepsia guideline. We suggest that patients ≥60 years of age presenting with dyspepsia are investigated with upper gastrointestinal endoscopy to exclude organic pathology. This is a conditional recommendation and patients at higher risk of malignancy (such as spending their childhood in a high risk gastric cancer country or having a positive family history) could be offered an endoscopy at a younger age. Alarm features should not automatically precipitate endoscopy in younger patients but this should be considered on a case-by-case basis. We recommend patients <60 years of age have a non-invasive test Helicobacter pylori and treatment if positive. Those that are negative or do not respond to this approach should be given a trial of proton pump inhibitor (PPI) therapy. If these are ineffective tricyclic antidepressants (TCA) or prokinetic therapies can be tried. Patients that have an endoscopy where no pathology is found are defined as having functional dyspepsia (FD). H. pylori eradication should be offered in these patients if they are infected. We recommend PPI, TCA and prokinetic therapy (in that order) in those that fail therapy or are H. pylori negative. We do not recommend routine upper gastrointestinal (GI) motility testing but it may be useful in selected patients.
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Affiliation(s)
- Paul Moayyedi
- Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | - Brian E Lacy
- Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | | | - Robert A Enns
- Division of Gastroenterology, St Paul's Hospital, University of British Columbia, Pacific Gastroenterology Associates, Vancouver, British Columbia, Canada
| | - Colin W Howden
- Division of Gastroenterology, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Nimish Vakil
- University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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26
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Dennie J, Atiee G, Warren V, Tao B, Morimoto K, Senaldi G. A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of DS-3801b, a Motilin Receptor Agonist, in Healthy Subjects. J Clin Pharmacol 2017; 57:1221-1230. [DOI: 10.1002/jcph.919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 03/17/2017] [Indexed: 01/24/2023]
Affiliation(s)
| | | | | | - Ben Tao
- Daiichi Sankyo Inc.; Edison NJ USA
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27
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Camilleri M, Bueno L, Andresen V, De Ponti F, Choi MG, Lembo A. Pharmacological, Pharmacokinetic, and Pharmacogenomic Aspects of Functional Gastrointestinal Disorders. Gastroenterology 2016; 150:S0016-5085(16)00220-1. [PMID: 27144621 DOI: 10.1053/j.gastro.2016.02.029] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 02/09/2016] [Indexed: 02/08/2023]
Abstract
This article reviews medications commonly used for the treatment of patients with functional gastrointestinal disorders. Specifically, we review the animal models that have been validated for the study of drug effects on sensation and motility; the preclinical pharmacology, pharmacokinetics, and toxicology usually required for introduction of new drugs; the biomarkers that are validated for studies of sensation and motility endpoints with experimental medications in humans; the pharmacogenomics applied to these medications and their relevance to the FGIDs; and the pharmacology of agents that are applied or have potential for the treatment of FGIDs, including psychopharmacologic drugs.
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Affiliation(s)
- Michael Camilleri
- Professor of Medicine, Pharmacology, and Physiology, Mayo Clinic College of Medicine, Consultant in Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Viola Andresen
- Israelitic Hospital, University of Hamburg, Orchideenstieg 14, Hamburg, Germany
| | - Fabrizio De Ponti
- Professor of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Myung-Gyu Choi
- Professor of Gastroenterology, The Catholic University of Korea College of Medicine Internal Medicine , President, Korean Society of Neurogastroenterology and Motility , Seoul, Korea
| | - Anthony Lembo
- Associate Professor, Harvard Medical School, Director of the GI Motility Laboratory at the Beth Israel Deaconess Medical Center's (BIDMC) Division of Gastroenterology, Boston, MA, USA
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28
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DiBaise JK, Patel N, Noelting J, Dueck AC, Roarke M, Crowell MD. The relationship among gastroparetic symptoms, quality of life, and gastric emptying in patients referred for gastric emptying testing. Neurogastroenterol Motil 2016; 28:234-42. [PMID: 26547484 DOI: 10.1111/nmo.12718] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 10/06/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Symptoms suggestive of gastroparesis are non-specific and conflicting reports exist regarding the ability of symptoms to predict the presence of gastroparesis. Our aim, therefore, was to evaluate the relationships between gastroparetic symptoms and their impact on quality of life and determine their relationship with clinical factors and gastric emptying. METHODS Gastric emptying scintigraphy, sociodemographic features, health care resource utilization, gastroparetic symptoms, and quality of life using validated questionnaires were obtained from consecutive patients referred for gastric emptying testing (GET). Descriptive analyses were conducted and logistic regression was performed to evaluate associations with abnormal gastric emptying after controlling for other covariates. KEY RESULTS Two hundred and sixty-six patients participated (195 females; mean age, 49.1 ± 17.6 years); 75% met Rome III criteria for functional dyspepsia. Gastric emptying was delayed in 28.2% at 4 h; the delay was mild in 48%, moderate in 20% and severe in 32%. Nausea/emesis and postprandial fullness, but not bloating, were significantly greater in those with delayed emptying. Postprandial fullness was most severe. Weak correlations were identified between symptom severity and the severity of gastric emptying delay. Quality of life was also lower in the delayed emptying group. Logistic regression analysis demonstrated associations between delayed gastric emptying and lower quality of life and increased symptom severity. CONCLUSIONS & INFERENCES In patients referred for GET, gastroparetic symptoms were more severe in those with delayed emptying. A decrease in quality of life in those with delayed gastric emptying was also present; this was not related to the severity of the delay in gastric emptying.
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Affiliation(s)
- J K DiBaise
- Department of Gastroenterology, Mayo Clinic, Scottsdale, AZ, USA
| | - N Patel
- Department of Gastroenterology, Mayo Clinic, Scottsdale, AZ, USA
| | - J Noelting
- Department of Gastroenterology, Mayo Clinic, Scottsdale, AZ, USA
| | - A C Dueck
- Department of Biostatistics, Mayo Clinic, Scottsdale, AZ, USA
| | - M Roarke
- Department of Radiology, Mayo Clinic, Scottsdale, AZ, USA
| | - M D Crowell
- Department of Gastroenterology, Mayo Clinic, Scottsdale, AZ, USA
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Tack J, Corsetti M. Ghrelin Agonists as Emerging Prokinetic Agents. Clin Gastroenterol Hepatol 2015; 13:2320-2. [PMID: 26343182 DOI: 10.1016/j.cgh.2015.08.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 08/26/2015] [Accepted: 08/27/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Jan Tack
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
| | - Maura Corsetti
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
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30
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Zhao X, Mashimo H. Current and Emerging Medical Therapies for Gastroparesis. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2015; 13:452-72. [PMID: 26507073 DOI: 10.1007/s11938-015-0071-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OPINION STATEMENT Gastroparesis likely involves various pathophysiological disorders and is increasingly prevalent as complications of surgeries, medications, and chronic diabetes. Key to diagnosis is evidence of delayed gastric emptying, generally based on standardized scintigraphy, and ruling out distal obstruction or other dysmotilities. Initial medical management includes reviewing potentially exacerbating medications and ruling out other reversible causes, achieving tighter glucose control in diabetics, and implementing dietary and lifestyle changes. While current available medications are limited, symptomatic control is aimed at improving gastric emptying, alleviating nausea and vomiting, and treating associated abdominal pain. Other potential therapies are aimed at reducing acid production, improving gastric accommodation or pyloric dysfunction, and treating bacterial overgrowth. Future studies should be aimed toward identification of subpopulations of gastroparetics who are better responders to the various medications based on differences in underlying pathophysiology and adopting standardized study end point measures that may allow for comparisons across trials. This chapter will review current treatment options, upcoming promising medications, and some of the hurdles in advancing the field forward.
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Affiliation(s)
- Xiaofeng Zhao
- Center for Swallowing and Motility Disorders, VA Boston Healthcare/Harvard Medical School, 1400 VFW Pkwy, West Roxbury, MA, 02132, USA
| | - Hiroshi Mashimo
- Center for Swallowing and Motility Disorders, VA Boston Healthcare/Harvard Medical School, 1400 VFW Pkwy, West Roxbury, MA, 02132, USA.
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Abstract
PURPOSE OF REVIEW Structural causes are absent in more than 50% of patients with symptoms referred to the gastroduodenal region when routine diagnostic tests are applied. New knowledge holds the prospect that targeted therapy may more optimally manage subsets of these patients with functional dyspepsia. RECENT FINDINGS An understanding of gut-to-brain and brain-to-gut pathways in functional dyspepsia is expanding. Minimal mucosal inflammation with eosinophils (and in some cases mast cells) characterized by ultrastructural changes in the duodenum appears to be present in a substantial subgroup of functional dyspepsia patients as identified now by investigators globally. Although antibiotic therapy targeting Helicobacter pylori appears to be effective in a small proportion of functional dyspepsia patients, eradication therapy may be more effective in functional dyspepsia patients with microscopic duodenal inflammation, a potentially important finding needing to be confirmed. This may suggest that the effects of antibiotics for functional dyspepsia are not simply mediated by the eradication of gastric H. pylori, but have other antibacterial effects (e.g., on the duodenal microbiome). Abnormal visceral sensory function plays a key role not only in the manifestations of functional dyspepsia but also in peptic ulcer disease. SUMMARY The pathophysiologic concepts underlying functional dyspepsia and related treatment approaches are shifting from a focus on H. pylori, acid suppression or modulation of motility toward new models. New evidence suggests that minimal duodenal inflammation plays a role in symptom generation in at least a proportion of patients with otherwise unexplained symptoms. This is a paradigm shift and ultimately may change the treatment of many patients with functional gastrointestinal disorders.
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Affiliation(s)
- Gerald Holtmann
- aFaculty of Medicine and Biomedical Sciences bFaculty of Health and Behavioural Sciences, Princess Alexandra Hospital Brisbane cTranslational Research Institute, University of Queensland, Brisbane, Queensland dFaculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia
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Abstract
Gastroparesis is a heterogeneous disorder defined by delay in gastric emptying. Symptoms of gastroparesis are nonspecific, including nausea, vomiting, early satiety, bloating, and/or abdominal pain. Normal gastric motor function and sensory function depend on a complex coordination between the enteric and central nervous system. This article discusses the pathophysiology of delayed gastric emptying and the symptoms of gastroparesis, including antropyloroduodenal dysmotility, impaired gastric accommodation, visceral hypersensitivity, and autonomic dysfunction. The underlying pathophysiology of gastroparesis is complex and multifactorial. The article discusses how a combination of these factors leads to symptoms of gastroparesis.
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Pasricha PJ. Does the emptier have no clothes? Diabetes, gastric emptying, and the syndrome of gastroparesis. Clin Gastroenterol Hepatol 2015; 13:477-9. [PMID: 25451883 DOI: 10.1016/j.cgh.2014.10.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 10/29/2014] [Accepted: 10/29/2014] [Indexed: 02/07/2023]
Affiliation(s)
- Pankaj Jay Pasricha
- Johns Hopkins Center for Neurogastroenterology, Johns Hopkins School of Medicine, Baltimore, Maryland
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Abstract
INTRODUCTION Functional dyspepsia (FD) is a relatively common gastrointestinal clinical condition that remains poorly understood. Controversies remain regarding the definition, pathophysiology and optimum treatment. The current treatment of FD is limited and no established regimen is available. AREAS COVERED Recent advances have improved our understanding of the pathophysiology of the disease and have led to the development of newer tailored therapies. Novel agents such as the motilin receptor agonist camicinal and the muscarinic M1 and M2 receptor antagonist acotiamide appear promising; however, the need for a safe and efficacious treatment remains largely unmet. This review describes the currently available management options for FD and critically evaluates emerging therapies. EXPERT OPINION The optimal treatment for FD is yet to be determined. A proton pump inhibitor or a prokinetic agent constitutes primary treatment. Helicobacter pylori testing and eradication is recommended. Based on currently available data, acotiamide appears promising, particularly in postprandial distress syndrome. Further large-scale multicentered trials are required to define the duration of treatment and the side-effect profile.
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Affiliation(s)
- Alkesh V Zala
- John Hunter Hospital, Department of Gastroenterology, New Lambton Heights , Newcastle, NSW , Australia
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35
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Zai H, Matsueda K, Kusano M, Urita Y, Saito Y, Kato H. Effect of acotiamide on gastric emptying in healthy adult humans. Eur J Clin Invest 2014; 44:1215-21. [PMID: 25370953 DOI: 10.1111/eci.12367] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 10/31/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Acotiamide is a first-in-class drug that is used to treat functional dyspepsia (FD). It is considered that acotiamide acts as an antagonist on muscarinic autoreceptors in the enteric nervous system and inhibits acetylcholinesterase activity. We examined the effect of acotiamide on gastric emptying in healthy adult humans. MATERIALS AND METHODS Twelve healthy adult males were enrolled in this double-blind crossover study. Acotiamide or placebo was administered orally in the 12 subjects 30 min before ingestion of a nutritional liquid meal (400 Kcal/400 mL). Six of the 12 participants took 100 mg of acotiamide or placebo, and six of the 12 participants took 300 mg of acotiamide or placebo in a double-blind crossover fashion. All subjects underwent measurement of gastric emptying by the (13) C breath test. RESULTS After the meal with placebo was ingested, the %dose/h curve ascended. The %dose/h curve after a meal with 100 or 300 mg of acotiamide ascended in an identical manner compared with the results with placebo. No significant differences were observed at any studied time point, and there were no significant changes in gastric emptying parameters (gastric emptying coefficient, t-1/2ex and t-lag ex). CONCLUSIONS A single administration of 100 or 300 mg of acotiamide did not affect gastric emptying after a liquid meal in healthy adult humans. Acotiamide has profound effects on restoring delayed gastric emptying and impaired accommodation in patients with FD but may have no effect on gastric emptying in healthy subjects. Such pharmacological actions have not been observed in previous gastroprokinetic studies.
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Affiliation(s)
- Hiroaki Zai
- Department of General Medicine and Emergency Care, Faculty of Medicine, School of Medicine, Toho University, Tokyo, Japan
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Nguyen NQ. Pharmacological therapy of feed intolerance in the critically ills. World J Gastrointest Pharmacol Ther 2014; 5:148-55. [PMID: 25133043 PMCID: PMC4133440 DOI: 10.4292/wjgpt.v5.i3.148] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 04/24/2014] [Accepted: 05/31/2014] [Indexed: 02/06/2023] Open
Abstract
Feed intolerance in the setting of critical illness is associated with higher morbidity and mortality, and thus requires promptly and effective treatment. Prokinetic agents are currently considered as the first-line therapy given issues relating to parenteral nutrition and post-pyloric placement. Currently, the agents of choice are erythromycin and metoclopramide, either alone or in combination, which are highly effective with relatively low incidence of cardiac, hemodynamic or neurological adverse effects. Diarrhea, however, can occur in up to 49% of patients who are treated with the dual prokinetic therapy, which is not associated with Clostridium difficile infection and settled soon after the cessation of the drugs. Hence, the use of prokinetic therapy over a long period or for prophylactic purpose must be avoided, and the indication for ongoing use of the drug(s) must be reviewed frequently. Second line therapy, such as total parenteral nutrition and post-pyloric feeding, must be considered once adverse effects relating the prokinetic therapy develop.
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Nguyen NQ, Yi Mei SLC. Current issues on safety of prokinetics in critically ill patients with feed intolerance. Ther Adv Drug Saf 2014; 2:197-204. [PMID: 25083212 DOI: 10.1177/2042098611415567] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Feed intolerance in the setting of critical illness should be treated promptly given its adverse impact on morbidity and mortality. The technical difficulty of postpyloric feeding tube placement and the morbidities associated with parenteral nutrition prevent these approaches being considered as first-line nutrition. Prokinetic agents are currently the mainstay of therapy for feed intolerance in the critically ill. Current information is limited but suggests that erythromycin or metoclopramide (alone or in combination) are effective in the management of feed intolerance in the critically ill and not associated with significant cardiac, haemodynamic or neurological adverse effects. However, diarrhoea is a very common gastrointestinal side effect, and can occur in up to 49% of patients who receive both erythromycin and metoclopramide. Fortunately, the diarrhoea associated with prokinetic treatments has not been linked to Clostridium difficile infection and settles soon after the drugs are ceased. Therefore, prolonged or prophylactic use of prokinetics should be avoided. If diarrhoea occurs, the drugs should be stopped immediately. To minimize avoidable adverse effects the ongoing need for prokinetic drugs in these patient should be reviewed daily.
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Affiliation(s)
- Nam Q Nguyen
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia
| | - Swee Lin Chen Yi Mei
- Departments of Gastroenterology and Hepatology, Royal Adelaide Hospital; Adelaide, SA, Australia
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Schaub N, Ng K, Kuo P, Aziz Q, Sifrim D. Gastric and lower esophageal sphincter pressures during nausea: a study using visual motion-induced nausea and high-resolution manometry. Am J Physiol Gastrointest Liver Physiol 2014; 306:G741-7. [PMID: 24627564 DOI: 10.1152/ajpgi.00412.2013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nausea is the subjective unpleasant sensation that immediately precedes vomiting. Studies using barostats suggest that gastric fundus and lower esophageal sphincter (LES) relaxation precede vomiting. Unlike barostat, high-resolution manometry allows less invasive, detailed measurements of fundus pressure (FP) and axial movement of the gastroesophageal junction (GEJ). Nausea was induced in 12 healthy volunteers by a motion video and rated on a visual analog scale. FP was measured as the mean value of the five pressure channels that were clearly positioned below the LES. After intubation, a baseline (BL) recording of 15 min was obtained. This was followed by presentation of the motion video (at least 10 min, maximum 20 min) followed by 30 min recovery recording. Throughout the experiment we recorded autonomic nervous system (ANS) parameters [blood pressure, heart rate (HR), and cardiac vagal tone (CVT), which reflects efferent vagal activity]. Ten out of 12 subjects showed a drop in FP during peak nausea compared with BL (-4.0 ± 0.8 mmHg; P = 0.005), and 8/10 subjects showed a drop in LES pressure (-8.8 ± 2.5 mmHg; P = 0.04). Peak nausea preceded peak fundus and LES pressure drop. Nausea was associated with configuration changes at the GEJ such as LES shortening and esophageal lengthening. During nausea we observed a significantly increased HR and decreased CVT. In conclusion, nausea is associated with a drop in fundus and LES pressure, configuration changes at the GEJ as well as changes in the ANS activity such as an increased sympathetic tone (increased HR) and decreased parasympathetic tone (decreased CVT).
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Affiliation(s)
- Nora Schaub
- Neurogastroenterology Group, Center for Digestive Diseases, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Antecolic versus retrocolic route of the gastroenteric anastomosis after pancreatoduodenectomy: a randomized controlled trial. Ann Surg 2014; 259:45-51. [PMID: 24096769 DOI: 10.1097/sla.0b013e3182a6f529] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To investigate the relationship between the route of gastroenteric (GE) reconstruction after pancreatoduodenectomy (PD) and the postoperative incidence of delayed gastric emptying (DGE). BACKGROUND DGE is one of the most common complications after PD. Recent studies suggest that an antecolic route of the GE reconstruction leads to a lower incidence of DGE, compared to a retrocolic route. In a nonrandomized comparison within our trial center, we found no difference in DGE after antecolic or retrocolic GE reconstruction. METHODS Ten middle- to high-volume centers participated in the patient inclusion. Patients scheduled for PD who gave written informed consent were included and randomized during surgery after resection. Standard operation was a pylorus-preserving PD. Primary endpoint was DGE. Secondary endpoints included other complications and length of hospital stay. RESULTS There were 125 patients in the retrocolic group, and 121 patients in the antecolic group. Baseline and treatment characteristics did not differ between the study groups. In the retrocolic group, 45 patients (36%) developed clinically relevant DGE compared with 41 (34%) in the antecolic group (absolute risk difference: 2.1%; 95% confidence interval: -9.8% to 14.0%). There were no differences in need for postoperative (par)enteral nutritional support, other complications, hospital mortality, and median length of hospital stay. CONCLUSIONS The route of GE reconstruction after PD does not influence the postoperative incidence of DGE or other complications. The etiology and treatment of DGE, which occurs frequently after both procedures, need further investigation. The GE reconstruction after PD should be routed according to the surgeon's preference.
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Camilleri M, Acosta A. A ghrelin agonist fails to show benefit in patients with diabetic gastroparesis: let's not throw the baby out with the bath water. Neurogastroenterol Motil 2013; 25:859-63. [PMID: 24001134 DOI: 10.1111/nmo.12226] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 08/08/2013] [Indexed: 02/08/2023]
Abstract
Ghrelin is the endogenous ligand for the growth hormone secretagogue-1a receptor and is a potential target for treatment of gastroparesis. This viewpoint assesses the potential role of ghrelin agonists in the treatment of gastroparesis through a review of the early phase, randomized, controlled trials of ghrelin agonists in patients with diabetes and, either, delayed gastric emptying at the time of the trial or symptoms at the time of the trial, and prior documentation of delayed gastric emptying of solids. Whereas recent experience with ghrelin agonists that have a macrocycle structure (TZP-101, TZP-102) has not confirmed earlier promising results, there is little evidence that ghrelin receptors downregulate with repeated treatment, in contrast to motilin receptors. Phase IIa clinical trials performed with a different agent (RM-131, which is a small molecule ghrelin agonist) suggest that, as a class, ghrelin agonists may be efficacious in stimulating gastric emptying. It is premature to dismiss ghrelin agonists as potential therapies for gastroparesis.
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Affiliation(s)
- M Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN, USA
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Bashashati M, McCallum RW. Neurochemical mechanisms and pharmacologic strategies in managing nausea and vomiting related to cyclic vomiting syndrome and other gastrointestinal disorders. Eur J Pharmacol 2013; 722:79-94. [PMID: 24161560 DOI: 10.1016/j.ejphar.2013.09.075] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Revised: 09/24/2013] [Accepted: 09/27/2013] [Indexed: 12/18/2022]
Abstract
Nausea and vomiting are common gastrointestinal complaints which could be triggered by stimuli in both the peripheral and central nervous systems. They may be considered as defense mechanisms when threatening toxins/agents enter the gastrointestinal tract or there is excessive retention of gastrointestinal contents due to obstruction. The pathophysiology of nausea and vomiting is complex and much still remains unknown. Therefore, treatments are restricted or ineffective in many cases. Nausea and vomiting with functional etiologies including cyclic vomiting syndrome are challenging in gastroenterology. In this article, we review potential pathways, neurochemical transmitters, and their receptors which are possibly involved in the pathophysiology of nausea and vomiting including the entity cyclic vomiting syndrome.
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Affiliation(s)
- Mohammad Bashashati
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Richard W McCallum
- Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
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Abstract
Severe gastroparesis is a kind of gastroparesis that is refractory to conventional drug therapy and requires nutritional support and frequently emergency hospitalization. The selection of treatment for severe gastroparesis has always been a dilemma for clinicians. Currently, there have been limited reports on the treatment of severe gastroparesis. This article sums up the primary treatments, drug treatments and other kinds of treatments for severe gastroparesis and discusses the prospects for the treatment of this refractory disease.
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Luttikhold J, de Ruijter FM, van Norren K, Diamant M, Witkamp RF, van Leeuwen PAM, Vermeulen MAR. Review article: the role of gastrointestinal hormones in the treatment of delayed gastric emptying in critically ill patients. Aliment Pharmacol Ther 2013; 38:573-83. [PMID: 23879699 DOI: 10.1111/apt.12421] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 12/27/2012] [Accepted: 07/01/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Delayed gastric emptying limits the administration of enteral nutrition, leading to malnutrition, which is associated with higher mortality and morbidity. Currently available prokinetics have limitations in terms of sustained efficacy and side effects. AIM To summarise the mechanisms of action and to discuss the possible utility of gastrointestinal hormones to prevent or treat delayed gastric emptying in critically ill patients. METHODS We searched PubMed for articles discussing 'delayed gastric emptying', 'enteral nutrition', 'treatment', 'gastrointestinal hormones', 'prokinetic', 'agonist', 'antagonist' and 'critically ill patients'. RESULTS Motilin and ghrelin receptor agonists initiate the migrating motor complex in the stomach, which accelerates gastric emptying. Cholecystokinin, glucagon-like peptide-1 and peptide YY have an inhibiting effect on gastric emptying; therefore, antagonising these gastrointestinal hormones may have therapeutic potential. Other gastrointestinal hormones appear less promising. CONCLUSIONS Manipulation of endogenous secretion, physiological replacement and administration of gastrointestinal hormones in pharmacological doses is likely to have therapeutic potential in the treatment of delayed gastric emptying. Future challenges in this field will include the search for candidates with improved selectivity and favourable kinetic properties.
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Affiliation(s)
- J Luttikhold
- Department of Surgery, VU University Medical Center, Amsterdam, the Netherlands.
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Stevens JE, Jones KL, Rayner CK, Horowitz M. Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives. Expert Opin Pharmacother 2013; 14:1171-1186. [PMID: 23663133 DOI: 10.1517/14656566.2013.795948] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Gastroparesis is an important clinical disorder characterised by delayed gastric emptying in the absence of mechanical outlet obstruction. Idiopathic, diabetes and postsurgical causes represent the most common aetiologies. The condition commonly manifests as upper gastrointestinal symptoms, including nausea, vomiting, postprandial fullness, early satiety, abdominal pain and bloating. AREAS COVERED This paper provides a review of the prevalence, pathophysiology and clinical features associated with gastroparesis, with a particular focus on current pharmacological management options and novel and emerging therapies. A literature search was undertaken using the search terms: gastroparesis, diabetic gastroparesis, idiopathic gastroparesis, gastric emptying, prokinetic, metoclopramide, domperidone, erythromycin, motilin, alemcinal, KC11458, mitemcinal, ghrelin, TZP-101, TZP-102, RM-131, tegaserod, prucalopride, naronapride, velusetrag, levosulpiride, itopride, botulinum toxin, gastric electrical stimulation, Enterra. EXPERT OPINION Strategies for the management of gastroparesis include correction of malnutrition, dehydration and electrolyte imbalance, relief of symptoms by appropriate use of prokinetic and antiemetic agents and, in patients with gastroparesis associated with diabetes or critical illness-induced hyperglycaemia, optimisation of glycaemic control. Conventional prokinetic agents form the mainstay of treatment. While novel pharmacotherapies are in development, compelling evidence for their efficacy, particularly in symptom relief, remains to be established.
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Affiliation(s)
- Julie E Stevens
- University of South Australia, School of Pharmacy and Medical Sciences, Adelaide, Australia.
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Liu B, Piao X, Guo L. Effect of herbal formula Xiao Pi-II on functional dyspepsia. J TRADIT CHIN MED 2013; 33:298-302. [DOI: 10.1016/s0254-6272(13)60168-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Quigley EMM, Lacy BE. Overlap of functional dyspepsia and GERD--diagnostic and treatment implications. Nat Rev Gastroenterol Hepatol 2013; 10:175-86. [PMID: 23296247 DOI: 10.1038/nrgastro.2012.253] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
GERD and functional dyspepsia are the two most prevalent upper gastrointestinal disorders. Gastro-oesophageal reflux is most commonly diagnosed using the cardinal symptoms of heartburn and regurgitation. Patients might also be diagnosed using a questionnaire, after empiric treatment with an acid suppressant, after upper endoscopy or by pH testing. Functional dyspepsia is best diagnosed using symptoms outlined by the Rome committee in conjunction with a normal upper endoscopy. Theoretically, distinguishing these two populations should be easy for all health-care providers. In reality, however, carefully separating out these two populations can be quite difficult, as substantial overlap exists epidemiologically, symptomatically and even diagnostically. This overlap renders precise diagnosis a challenge; given the limited treatment options, the primary goal is to identify those patients who will respond to acid suppressive therapy. Despite the frequency with which functional dyspepsia and GERD overlap, remarkably few studies have investigated this overlap. Most recommendations are based on data derived from separate studies of functional dyspepsia and GERD. A further limitation of existing studies is their failure to differentiate between the various diagnostic categories into which the individual presenting with heartburn might belong.
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Abstract
Functional dyspepsia refers to painful and nonpainful symptoms that are perceived to arise in the upper digestive tract but are not secondary to organic, systemic or metabolic diseases. The symptoms of this syndrome often overlap with those of GERD and IBS, making its management far from simple. If Helicobacter pylori infection is diagnosed in patients with functional dyspepsia, it should be treated. In patients with mild or intermittent symptoms, reassurance and lifestyle advice might be sufficient; in patients not responding to these measures, or in those with more severe symptoms, drug therapy should be considered. Both PPIs and prokinetics can be used in initial empirical pharmacotherapy based on symptom patterns--a PPI is more likely to be effective in the presence of retrosternal or epigastric burning or epigastric pain, whereas a prokinetic is more effective in dyspepsia with early satiation or postprandial fullness. Although combinations of PPIs and prokinetics might have additive symptomatic effects, single-drug therapy is initially preferable. Antidepressants or referral to a psychiatrist or psychotherapist can be considered in nonresponders and in those whose symptoms have a marked effect on daily functioning. Despite extensive research, functional dyspepsia treatment often remains unsatisfactory. Better characterization of dyspeptic subgroups and understanding of underlying mechanisms will enable treatment advances to be made in the future.
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Depoortere I. Can small non-peptide motilin agonists force a breakthrough as gastroprokinetic drugs? Br J Pharmacol 2013; 167:760-2. [PMID: 22616752 DOI: 10.1111/j.1476-5381.2012.02046.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
GSK962040 is a small selective motilin receptor agonist currently under investigation in clinical trials for the treatment of conditions associated with delayed gastric emptying. As reported in this issue of the British Journal of Pharmacology, Broad et al., studied for the first time the region-dependent contractile effects of motilin and GSK962040 in human smooth muscle strips. Both compounds facilitated cholinergically mediated contractions of human gastric antral muscle strips at low concentrations and induced smooth muscle contractions at high concentrations. The effect was less pronounced in the fundus and almost absent in the colon. The long-lasting facilitation of cholinergic responses in the antrum by GSK962040 compared with the fading responses to motilin may be of importance from a clinical point of view. The approach used by Broad et al. with human tissue is a validated model to identify motilin receptor agonists with therapeutic value.
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Affiliation(s)
- Inge Depoortere
- Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Herestraat 49, Leuven, Belgium.
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Utsunomiya S, Matsuura B, Ueda T, Miyake T, Furukawa S, Kumagi T, Ikeda Y, Abe M, Hiasa Y, Onji M. Critical residues in the transmembrane helical bundle domains of the human motilin receptor for erythromycin binding and activity. ACTA ACUST UNITED AC 2013; 180:17-25. [DOI: 10.1016/j.regpep.2012.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Revised: 08/26/2012] [Accepted: 10/17/2012] [Indexed: 01/31/2023]
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