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Abstract
Gastroparesis is a neurogastrointestinal disorder of motility in which patients experience symptoms of nausea, vomiting, bloating, early satiety, postprandial fullness, upper abdominal discomfort or pain, and delayed gastric emptying of solids based on scintigraphy or stable isotope breath test when mechanical obstruction has been excluded. Symptoms of gastroparesis may result from diverse pathophysiological mechanisms, including antroduodenal hypomotility, pylorospasm, increased gastric accommodation, and visceral hypersensitivity. The most common etiologies of gastroparesis are idiopathic, diabetic, and postsurgical, and less frequent causes are neurodegenerative disorders (Parkinson's disease), myopathies (scleroderma, amyloidosis), medication-induced (glucagon-like peptide-1 agonists and opioid agents), and paraneoplastic syndrome. This review addresses pharmacologic management of gastroparesis including prokinetic and antiemetic agents, pharmacologic agents targeting the pylorus, and effects of neuromodulators. SIGNIFICANCE STATEMENT: Gastroparesis is a neurogastrointestinal motility disorder characterized by delayed gastric emptying without mechanical obstruction with numerous upper gastrointestinal symptoms, including nausea and vomiting. The management of gastroparesis involves nutritional support, medications, and procedures. The only Food and Drug Administration-approved medication for gastroparesis is metoclopramide. This article reviews the pharmacology and efficacy of all classes of antiemetics or prokinetic effects used in gastroparesis. There is still a considerable unmet need for efficacious medications specifically for the treatment of gastroparesis, especially in refractory cases.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Kara J Jencks
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Zhu YN, Ren YD, Li L, Niu YQ, Wang RR, Li M. Plasma levels of ghrelin, neuropeptide Y, and urocortin-1 in patients with different subtypes of functional dyspepsia. Shijie Huaren Xiaohua Zazhi 2025; 33:62-69. [DOI: 10.11569/wcjd.v33.i1.62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/29/2024] [Accepted: 12/27/2024] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Functional dyspepsia (FD) is a common disease of the digestive system, and its burden on medical resources is increasing year by year. Brain-gut axis dysfunction is considered to be an important pathogenesis of the disease, and brain-gut peptide plays an important role in the regulation of the brain-gut axis. In this study, plasma levels of acyl ghrelin (AG), desacyl ghrelin (DAG), neuropeptide Y (NPY), and urocortin-1 (UCN-1) were measured, and generalized Anxiety Disorder Scale and Patient Health Questionnaire Depression Scale were used to assess the psychosocial status of patients to reveal their differences among different FD subtypes.
AIM To determine the plasma levels of AG, DAG, NPY and UCN-1 in patients with different subtypes of FD, and to investigate the psychosocial status of patients with FD, in order to find effective theoretical support for clinical treatment.
METHODS From February 2022 to March 2023, 53 patients with FD (all meeting Rome IV diagnostic criteria) were selected from the Department of Gastroenterology of the Second Hospital of Tianjin Medical University, including 19 cases in postprandial discomfort syndrome (PDS) group, 19 cases in overlap syndrome group, and 15 cases in epigastric pain syndrome (EPS) group. Fifteen healthy volunteers who underwent medical check-ups during the same time period were selected as a healthy control group. All study subjects were tested for plasma AG, DAG, NPY, and UCN-1 levels by enzyme-linked immunoassay, and four scales, namely, the Nepean Dyspepsia Symptom Index Rating Scale, Nepean Quality of Life Index Rating Scale, Generalized Anxiety Disorder Scale, and Patient Health Questionnaire Depression Scale, were used to assess the psychosocial status of the subjects.
RESULTS The level of serum AG in the PDS group was lower than those of the control (P < 0.001), EPS (P < 0.001), and overlap syndrome groups (P = 0.030). The level of serum AG in the overlap syndrome group was lower than those of the control (P = 0.017) and EPS groups (P = 0.008). However, no significant difference was found in serum AG between the EPS and control groups (P = 0.684). The differences in plasma DAG levels were not significant between the PDS and control groups (P = 0.458), between the EPS and control groups (P = 0.638), between the overlap syndrome and control groups (P = 0.612), between the PDS and EPS groups (P = 0.170), between the PDS and overlap syndrome groups (P = 0.709), and between the EPS and overlap syndrome groups (P = 0.239). The level of serum NPY in the PDS group was lower than those of the control (P = 0.043), EPS (P = 0.044), and overlap syndrome groups (P = 0.049), but no significant difference was found between the EPS and control groups (P = 0.971), between the EPS and overlap syndrome groups (P = 0.929), and between the overlap syndrome and control groups (P = 0.929). The level of serum UCN-1 in the PDS group was higher than those of the control (P = 0.036), EPS (P = 0.015), and overlap syndrome groups (P = 0.045), but no significant difference was found between the the EPS and control groups (P = 0.978), between the EPS and overlap syndrome groups (P = 0.571), and between the overlap syndrome and control groups (P = 0.649). The difference in the levels of anxiety and depression was statistically different between the FD group and the control group (P < 0.001), but the difference was not statistically significant between any two of the FD subgroups (P = 0.471 for anxiety, P = 0.171 for depression).
CONCLUSION Except between the EPS group and the healthy control group, the differences in plasma AG between any two of the other groups are statistically significant, suggesting that AG may be crucial in the pathogenesis of FD and its level can predict the clinical manifestations of FD. There is no significant difference in plasma DAG between any two of the groups, suggesting that DAG might not be involved in the pathogenesis of FD. Compared with the other three groups, the differences of plasma AG, NPY, and UCN-1 in the PDS group were statistically significant, suggesting that these three brain and intestinal peptides may be involved in the pathogenesis of PDS. FD patients are more likely to be complicated with anxiety and depression, and the more severe the dyspepsia symptoms of FD patients, the more serious the degree of anxiety and depression, and the greater the impact on the quality of life, suggesting that improving patients' emotional problems is very helpful to improve the long-term efficacy for FD.
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Affiliation(s)
- Ya-Na Zhu
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Ya-Di Ren
- Department of Gastroenterology, Handan Central Hospital, Handan 056000, Hebei Province, China
| | - Lu Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Yan-Qing Niu
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Rao-Rao Wang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Man Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
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Zhu YN, Ren YD, Li L, Niu YQ, Wang RR, Li M. Plasma levels of ghrelin, neuropeptide Y, and urocortin-1 in patients with different subtypes of functional dyspepsia. Shijie Huaren Xiaohua Zazhi 2025; 33:60-67. [DOI: 10.11569/wcjd.v33.i1.60] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/29/2024] [Accepted: 12/27/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Functional dyspepsia (FD) is a common disease of the digestive system, and its burden on medical resources is increasing year by year. Brain-gut axis dysfunction is considered to be an important pathogenesis of the disease, and brain-gut peptide plays an important role in the regulation of the brain-gut axis. In this study, plasma levels of acyl ghrelin (AG), desacyl ghrelin (DAG), neuropeptide Y (NPY), and urocortin-1 (UCN-1) were measured, and generalized Anxiety Disorder Scale and Patient Health Questionnaire Depression Scale were used to assess the psychosocial status of patients to reveal their differences among different FD subtypes.
AIM To determine the plasma levels of AG, DAG, NPY and UCN-1 in patients with different subtypes of FD, and to investigate the psychosocial status of patients with FD, in order to find effective theoretical support for clinical treatment.
METHODS From February 2022 to March 2023, 53 patients with FD (all meeting Rome IV diagnostic criteria) were selected from the Department of Gastroenterology of the Second Hospital of Tianjin Medical University, including 19 cases in postprandial discomfort syndrome (PDS) group, 19 cases in overlap syndrome group, and 15 cases in epigastric pain syndrome (EPS) group. Fifteen healthy volunteers who underwent medical check-ups during the same time period were selected as a healthy control group. All study subjects were tested for plasma AG, DAG, NPY, and UCN-1 levels by enzyme-linked immunoassay, and four scales, namely, the Nepean Dyspepsia Symptom Index Rating Scale, Nepean Quality of Life Index Rating Scale, Generalized Anxiety Disorder Scale, and Patient Health Questionnaire Depression Scale, were used to assess the psychosocial status of the subjects.
RESULTS The level of serum AG in the PDS group was lower than those of the control (P < 0.001), EPS (P < 0.001), and overlap syndrome groups (P = 0.030). The level of serum AG in the overlap syndrome group was lower than those of the control (P = 0.017) and EPS groups (P = 0.008). However, no significant difference was found in serum AG between the EPS and control groups (P = 0.684). The differences in plasma DAG levels were not significant between the PDS and control groups (P = 0.458), between the EPS and control groups (P = 0.638), between the overlap syndrome and control groups (P = 0.612), between the PDS and EPS groups (P = 0.170), between the PDS and overlap syndrome groups (P = 0.709), and between the EPS and overlap syndrome groups (P = 0.239). The level of serum NPY in the PDS group was lower than those of the control (P = 0.043), EPS (P = 0.044), and overlap syndrome groups (P = 0.049), but no significant difference was found between the EPS and control groups (P = 0.971), between the EPS and overlap syndrome groups (P = 0.929), and between the overlap syndrome and control groups (P = 0.929). The level of serum UCN-1 in the PDS group was higher than those of the control (P = 0.036), EPS (P = 0.015), and overlap syndrome groups (P = 0.045), but no significant difference was found between the the EPS and control groups (P = 0.978), between the EPS and overlap syndrome groups (P = 0.571), and between the overlap syndrome and control groups (P = 0.649). The difference in the levels of anxiety and depression was statistically different between the FD group and the control group (P < 0.001), but the difference was not statistically significant between any two of the FD subgroups (P = 0.471 for anxiety, P = 0.171 for depression).
CONCLUSION Except between the EPS group and the healthy control group, the differences in plasma AG between any two of the other groups are statistically significant, suggesting that AG may be crucial in the pathogenesis of FD and its level can predict the clinical manifestations of FD. There is no significant difference in plasma DAG between any two of the groups, suggesting that DAG might not be involved in the pathogenesis of FD. Compared with the other three groups, the differences of plasma AG, NPY, and UCN-1 in the PDS group were statistically significant, suggesting that these three brain and intestinal peptides may be involved in the pathogenesis of PDS. FD patients are more likely to be complicated with anxiety and depression, and the more severe the dyspepsia symptoms of FD patients, the more serious the degree of anxiety and depression, and the greater the impact on the quality of life, suggesting that improving patients' emotional problems is very helpful to improve the long-term efficacy for FD.
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Affiliation(s)
- Ya-Na Zhu
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Ya-Di Ren
- Department of Gastroenterology, Handan Central Hospital, Handan 056000, Hebei Province, China
| | - Lu Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Yan-Qing Niu
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Rao-Rao Wang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
| | - Man Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin 300202, China
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Yang DY, Camilleri M. The goals for successful development of treatment in gastroparesis. Neurogastroenterol Motil 2024; 36:e14849. [PMID: 38884392 DOI: 10.1111/nmo.14849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/10/2024] [Accepted: 06/05/2024] [Indexed: 06/18/2024]
Abstract
BACKGROUND Gastroparesis is a motility disorder of the stomach characterized by cardinal symptoms and delayed gastric emptying of solid food in the absence of mechanical obstruction. There is significant unmet need in its management, and essentially there are no medications approved for its treatment over four decades. PURPOSE The objectives of this review are to develop an understanding of the goals of treatment, the evidence-based criteria for treatment success based on the current scientific understanding of gastroparesis as well as patient response outcomes, and to propose evidence-based principles for the successful development of treatments for gastroparesis. Specifically, we discuss the pathophysiologic targets in gastroparesis, eligibility criteria for clinical trial participation based on validated gastric emptying studies, and the patient response outcome measures that have been validated to appraise effects of treatment on clinically relevant outcomes. These considerations lead to recommendations regarding eligibility, design, and duration of proof-of-efficacy studies, and to endorsing the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary as a validated patient response outcome and to justification of the shortening of proof-of-efficacy, placebo-controlled clinical trials to 4 weeks treatment duration after a baseline period. We believe that such approaches will increase the likelihood of successful assessment of efficacy of novel approaches to treating patients with gastroparesis.
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Affiliation(s)
- David Yi Yang
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Haseeb-Ul-Rasool M, Elhawary A, Saha U, Sethi A, Swaminathan G, Abosheaishaa H. Resolution of severe gastroparesis induced by parasympathetic surge following facial trauma: a case report. J Med Case Rep 2024; 18:248. [PMID: 38750592 PMCID: PMC11097562 DOI: 10.1186/s13256-024-04558-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Gastroparesis is a condition that affects the motility of the gastrointestinal (GI) tract, causing a delay in the emptying process and leading to nausea, vomiting, bloating, and upper abdominal pain. Motility treatment along with symptom management can be done using antiemetics or prokinetics. This study highlights the diagnostic and therapeutic challenges of gastroparesis and suggests a potential link between facial trauma and symptom remission, indicating the need for further investigation. CASE PRESENTATION A 46-year-old Hispanic man with hypertension, type 2 diabetes (T2D), and hyperlipidemia on amlodipine 10 mg, lisinopril 5 mg, empagliflozin 25 mg, and insulin glargine presented with a diabetic foot ulcer with probable osteomyelitis. During hospitalization, the patient developed severe nausea and vomiting. The gastroenterology team advised continuing antiemetic medicine and trying very small sips of clear liquids. However, the patient didn't improve. Therefore, the gastroenterology team was contacted again. They advised having stomach emptying tests to rule out gastroparesis as the source of emesis. In addition, they recommended continuing metoclopramide, and starting erythromycin due to inadequate improvement. Studies found a 748-min stomach emptying time. Normal is 45-90 min. An uneventful upper GI scope was done. Severe gastroparesis was verified, and the gastroenterology team advised a percutaneous jejunostomy or gastric pacemaker for gastroparesis. Unfortunately, the patient suffered a mechanical fall resulting in facial trauma. After the fall, the patient's nausea eased, and emesis stopped. He passed an oral liquids trial after discontinuation of erythromycin and metoclopramide. CONCLUSION This case exemplifies the difficulties in diagnosing and treating gastroparesis. An interesting correlation between parasympathetic surges and recovery in gastroparesis may be suggested by the surprising remission of symptoms following face injuries.
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Affiliation(s)
| | - Ahmed Elhawary
- Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals Queens, New York, USA
| | - Utsow Saha
- Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals Queens, New York, USA
| | - Arshia Sethi
- Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals Queens, New York, USA
| | - Gowri Swaminathan
- Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals Queens, New York, USA
| | - Hazem Abosheaishaa
- Icahn School of Medicine at Mount Sinai, NYC Health+Hospitals Queens, New York, USA.
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Zhang YX, Zhang YJ, Li M, Tian JX, Tong XL. Common Pathophysiological Mechanisms and Treatment of Diabetic Gastroparesis. J Neurogastroenterol Motil 2024; 30:143-155. [PMID: 38576367 PMCID: PMC10999838 DOI: 10.5056/jnm23100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/29/2023] [Accepted: 11/06/2023] [Indexed: 04/06/2024] Open
Abstract
Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. Clinical manifestations include postprandial fullness and epigastric discomfort, bloating, nausea, and vomiting. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of interstitial cells of Cajal, abnormalities in the neuro-endocrine system and hormone levels. Therefore, this study will review recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment of gastrointestinal motility disorders in order to give future research directions and identify treatment strategies for DGP.
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Affiliation(s)
- Yu-Xin Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yan-Jiao Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Li
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jia-Xing Tian
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiao-Lin Tong
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Camilleri M, Zheng T, Vosoughi K, Lupianez-Merly C, Eckert D, Busciglio I, Burton D, Dilmaghani S. Optimal measurement of gastric emptying of solids in gastroparesis or functional dyspepsia: evidence to establish standard test. Gut 2023; 72:2241-2249. [PMID: 37726164 PMCID: PMC10872889 DOI: 10.1136/gutjnl-2023-330733] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 08/31/2023] [Indexed: 09/21/2023]
Abstract
OBJECTIVE Symptoms in gastroparesis (Gp) and functional dyspepsia (FD) overlap; using egg protein substitute to measure gastric emptying of solids (GES), ~40% of patients are reclassified from Gp to FD, and vice versa. Our aim was to assess inter-individual and intra-individual coefficients of variation (COV) in GES in symptomatic patients with Gp or FD with documented slow or normal GES, respectively. DESIGN Scintigraphic GES (T1/2 and GE% at 2 and 4 hours) using a 320 kcal real egg meal (30% fat) was tested in the following: single measurements in 20 patients with diabetes mellitus (10 each type 1 and type 2); repeat GES to estimate COVintra measured: 3 days apart in 9 Gp, 4 weeks apart in 21 Gp and 18 with FD with normal GE assigned to placebo and in 70 patients at 94.3 weeks (median) apart. RESULTS COVinter for GE% at 4 hours and GE T1/2 were respectively 14.2% and 23.5% in FD and 27.5% and 33% in Gp; COVintra for GE% at 4 hours and GE T1/2 up to 4 weeks apart were 23.4% and 37.9% in FD and 20.1% and 33% in Gp. GE% at 2 hours showed less consistent results. However, >85% retained original diagnosis as normal or delayed. From clinical GES to baseline research for Gp group, repeat GES (after treatment) showed the COVintra for GE% at 4 hours was 37.3% at median 94.3 weeks, with 26/70 changed diagnoses. CONCLUSION The 320 kcal (30% fat) GES scintigraphic test provides consistent diagnosis in >85% and should be the standard test for suspected gastric emptying disorders.
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Affiliation(s)
| | - Ting Zheng
- Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | - Kia Vosoughi
- Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Deborah Eckert
- Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Duane Burton
- Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
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Wang S, Wang Y, Lin L, Li Z, Liu F, Zhu L, Chen J, Zhang N, Cao X, Ran S, Liu G, Gao P, Sun W, Peng L, Zhuang J, Meng H. Layer-Specific BTX-A Delivery to the Gastric Muscularis Achieves Effective Weight Control and Metabolic Improvement. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300822. [PMID: 37552813 PMCID: PMC10558648 DOI: 10.1002/advs.202300822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 07/03/2023] [Indexed: 08/10/2023]
Abstract
The rising incidence of health-endangering obesity constantly calls for more effective treatments. Gastric intramural injection of botulinum neurotoxin A (BTX-A) as a new modality carries great promise yet inconsistent therapeutic efficacy. A layer-specific delivery strategy enabled by dissolving microneedles is hence pioneered to investigate the working site of BTX-A and the resulting therapeutic effects. The drug-loaded tips of the layer-specific gastric paralysis microneedles (LGP-MN) rapidly release and achieve uniform distribution of BTX-A within the designated gastric wall layers. In an obesity rat model, the LGP-MNs not only prove safer than conventional injection, but also demonstrate consistently better therapeutic effects with muscular layer delivery, including 16.23% weight loss (3.06-fold enhancement from conventional injection), 55.20% slower gastric emptying rate, improved liver steatosis, lowered blood lipids, and healthier gut microbiota. Further hormonal study reveals that the elevated production of stomach-derived glucagon-like peptide-1 due to the muscularis-targeting LGP-MN treatment is an important contributor to its unique glucose tolerance-improving effect. This study provides clear indication of the gastric muscularis as the most favorable working site of BTX-A for weight loss and metabolic improvement purposes, and meanwhile suggests that the LGP-MNs could serve as a novel clinical approach to treat obesity and metabolic syndromes.
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Affiliation(s)
- Siqi Wang
- Department of General Surgery and Obesity and Metabolic Disease CenterChina–Japan Friendship HospitalBeijing100029China
| | - Yuqiong Wang
- Department of Mechanical and Automation EngineeringThe Chinese University of HongkongHongkong999077China
- School of Biological Science and Medical EngineeringBeihang UniversityBeijing100191China
| | - Long Lin
- Engineering College of Peking UniversityPeking universityBeijing100029China
- School of Mechanical and Electrical EngineeringBeijing University of Chemical TechnologyBeijing100029China
| | - Zongjie Li
- Shanghai Veterinary Research InstituteChinese Academy of Agricultural ScienceShanghai200241China
| | - Fengyi Liu
- School of Mechanical and Electrical EngineeringBeijing University of Chemical TechnologyBeijing100029China
| | - Long Zhu
- School of Mechanical and Electrical EngineeringBeijing University of Chemical TechnologyBeijing100029China
| | - Jie Chen
- Department of UltrasoundChina–Japan Friendship HospitalBeijing100029China
| | - Nianrong Zhang
- Department of General Surgery and Obesity and Metabolic Disease CenterChina–Japan Friendship HospitalBeijing100029China
| | - Xinyu Cao
- Department of General Surgery and Obesity and Metabolic Disease CenterChina–Japan Friendship HospitalBeijing100029China
| | - Sunman Ran
- Department of General Surgery and Obesity and Metabolic Disease CenterChina–Japan Friendship HospitalBeijing100029China
| | - Genzheng Liu
- Department of General Surgery and Obesity and Metabolic Disease CenterChina–Japan Friendship HospitalBeijing100029China
| | - Peng Gao
- Department of Clinical LaboratoryChina–Japan Friendship HospitalBeijing100029China
| | - Weiliang Sun
- Institute of Clinical Medical SciencesChina–Japan Friendship HospitalBeijing100029China
| | - Liang Peng
- Institute of Clinical Medical SciencesChina–Japan Friendship HospitalBeijing100029China
| | - Jian Zhuang
- School of Mechanical and Electrical EngineeringBeijing University of Chemical TechnologyBeijing100029China
| | - Hua Meng
- Department of General Surgery and Obesity and Metabolic Disease CenterChina–Japan Friendship HospitalBeijing100029China
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Zahid SA, Tated R, Mathew M, Rajkumar D, Karnik SB, Pramod Roy A, Jacob FP, Baskara Salian R, Razzaq W, Shivakumar D, Khawaja UA. Diabetic Gastroparesis and its Emerging Therapeutic Options: A Narrative Review of the Literature. Cureus 2023; 15:e44870. [PMID: 37814758 PMCID: PMC10560130 DOI: 10.7759/cureus.44870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 09/06/2023] [Indexed: 10/11/2023] Open
Abstract
Diabetic gastroparesis (DG) is one of the many complications of diabetes mellitus (DM). Even though this condition surfaces years after uncontrolled disease, it affects the quality of life in several ways and causes significant morbidity. Common symptoms experienced by the patients include postprandial nausea, vomiting, abdominal fullness, and pain. Strict glycemic control is essential to evade the effects of DG. The purpose of this review article is to briefly study the pathophysiology, clinical features, diagnostic modalities, and the effects of DG on different aspects of life. Furthermore, it also focuses on the emerging treatment modalities for DG. Tradipitant and relamorelin are two such treatment options that are gaining noteworthy recognition and are discussed in detail in this review article. As observed through various clinical trials, these drugs help alleviate symptoms like nausea, vomiting, abdominal pain, and bloating in patients suffering from DG, thereby targeting the most common and bothersome symptoms of the disease. This leads to an improvement in the quality of life, making it a reliable treatment option for this disease. But while pharmacological intervention is vital, psychological support and lifestyle changes are equally important and are the reason why a multidisciplinary approach is required for the treatment of DG.
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Affiliation(s)
- Shiza A Zahid
- Department of Internal Medicine, Jinnah Sindh Medical University, Karachi, PAK
| | - Ritu Tated
- Department of Internal Medicine, Mahatma Gandhi Mission Institute of Medical Sciences, Navi Mumbai, IND
| | - Midhun Mathew
- Department of Internal Medicine, Pennsylvania Hospital, Philadelphia, USA
| | - Daniel Rajkumar
- Department of Internal Medicine, Hospital Alor Gajah, Alor Gajah, MYS
| | - Siddhant B Karnik
- Department of Internal Medicine, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, IND
| | | | - Fredy P Jacob
- Department of Internal Medicine, Jonelta Foundation School of Medicine, University of Perpetual Help System DALTA, Las Piñas, PHL
| | | | - Waleed Razzaq
- Department of Internal Medicine, Services Hospital Lahore, Lahore, PAK
| | - Divya Shivakumar
- Department of Internal Medicine, Kamineni Academy of Medical Sciences and Research Center, Hyderabad, IND
| | - Uzzam Ahmed Khawaja
- Department of Paediatrics and Child Health, Aga Khan University Hospital, Karachi, PAK
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Ramos GP, Camilleri M. Ten controversies in gastroparesis and a look to the future. Neurogastroenterol Motil 2023; 35:e14494. [PMID: 36371704 PMCID: PMC10133001 DOI: 10.1111/nmo.14494] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/17/2022] [Accepted: 10/20/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Gastroparesis is a complex, challenging gastrointestinal disorder presenting with upper gastrointestinal symptoms, especially nausea and vomiting, with significant impact on patients' quality of life. After ruling out mechanical obstruction, it is essential to identify delay in gastric emptying for definitive diagnosis. The most common causes are idiopathic (no identified etiology), diabetes mellitus, and postsurgical status. Management of gastroparesis focuses on dietary modifications and treatment directed to symptom relief. Unfortunately, approximately one-third of patients are refractory to pharmacological therapy, and the effectiveness of the few nonpharmacological options has been questioned. PURPOSE Extensive review of the literature identifies several uncertainties or controversies regarding the differential diagnosis based on the spectrum of symptoms, the lack of availability of reliable diagnostic test, and questions regarding effective therapeutic options. In this review, we discuss ten controversies regarding gastroparesis: clinical presentation, diagnosis, overlap syndromes, pathophysiology, etiology, as well as pharmacological and nonpharmacological therapeutic options. In addition, we briefly review studies exploring pathological, inflammatory, and molecular disturbances affecting the intrinsic neuromuscular elements that may be involved in the pathophysiology of gastroparesis and may constitute possible therapeutic targets in the future. Finally, we tabulate future research opportunities to resolve these controversies in the management of patients with gastroparesis.
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Affiliation(s)
- Gabriela Piovezani Ramos
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
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11
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Goelen N, Jones M, Huang IH, Carbone F, Janssen P, Tack J. Do prokinetic agents provide symptom relief through acceleration of gastric emptying? An update and revision of the existing evidence. United European Gastroenterol J 2023; 11:146-162. [PMID: 36714973 PMCID: PMC10039797 DOI: 10.1002/ueg2.12362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Accepted: 01/02/2023] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Gastroparesis and functional dyspepsia are disorders characterized by upper gastrointestinal symptoms and multifaceted etiologies. One of the main therapeutic approaches is accelerating gastric emptying (GE) by means of prokinetic agents. Their efficacy has been demonstrated, although the association between symptom improvement and acceleration of emptying is less clear. Meta-analyses have found contradictory results. Differences in applied methodology and included trials might drive these contradictions. OBJECTIVE To provide a transparent meta-analysis update to elucidate the association between symptom improvement and acceleration of GE due to gastroprokinetic agents available for long-term use in patients with gastroparesis. DESIGN Two approaches from earlier meta-analyses were executed and compared. One analyzed the relative changes on active treatment versus baseline, the other compared the change from baseline on active treatment versus the change from baseline on placebo. Papers that reported sufficient numerical data for both analyses were selected. Both analyses included the same trials. RESULTS Overall, both approaches yield the same positive direction of association between symptom improvement and acceleration of emptying (0.291 (-0.391, 0.972), p = 0.4 and 0.453 (0.123, 0.782), p = 0.007 for the active-only and placebo-controlled analysis respectively). The association between symptom improvement and GE acceleration for studies using optimal GE tests was either 0.028 (p > 0.9) or 0.463 (p = 0.007), and for sub-optimal GE tests was either 0.370 (p = 0.4) or 0.052 (p > 0.9) depending on the used meta-analysis methodology. CONCLUSIONS The applied methodology for GE testing, and the meta-analysis substantially impacts the conclusion. When considering the clinically relevant outcome of improvement from baseline, symptoms and emptying improve with prokinetics, but no correlation is found between both aspects. When the change over placebo is considered, limiting the analysis to scientifically more rigorous study approaches, changes in emptying rate and symptom improvement are positively associated.
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Affiliation(s)
- Nick Goelen
- Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium
| | - Mike Jones
- Centre for Emotional Health, Psychology Department, Macquarie University, North Ryde, New South Wales, Australia
| | - I-Hsuan Huang
- Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium
| | - Florenca Carbone
- Department of Gastroenterology and Hepatology, Leuven University Hospitals, Leuven, Belgium
| | - Pieter Janssen
- Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium
- Department of Gastroenterology and Hepatology, Leuven University Hospitals, Leuven, Belgium
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12
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Camilleri M, Zheng T. Editorial: tradipitant has promise for treating gastroparesis but leaves gastric function alone-authors' reply. Aliment Pharmacol Ther 2022; 56:542-543. [PMID: 35804471 DOI: 10.1111/apt.17098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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13
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Abstract
Gastroparesis is characterized by symptoms suggesting retention of food in the stomach with objective evidence of delayed gastric emptying in the absence of mechanical obstruction in the gastric outflow. This condition is increasingly encountered in clinical practice. These guidelines summarize perspectives on the risk factors, diagnosis, and management of gastroparesis in adults (including dietary, pharmacological, device, and interventions directed at the pylorus), and they represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation process. When the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, we used expert consensus to develop key concept statements. These guidelines should be considered as preferred but are not the only approaches to these conditions.
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14
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Bukhari SNA. An insight into the multifunctional role of ghrelin and structure activity relationship studies of ghrelin receptor ligands with clinical trials. Eur J Med Chem 2022; 235:114308. [PMID: 35344905 DOI: 10.1016/j.ejmech.2022.114308] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/06/2022] [Accepted: 03/18/2022] [Indexed: 11/30/2022]
Abstract
Ghrelin is a multifunctional gastrointestinal acylated peptide, primarily synthesized in the stomach and regulates the secretion of growth hormone and energy homeostasis. It plays a central role in modulating the diverse biological, physiological and pathological functions in vertebrates. The synthesis of ghrelin receptor ligands after the finding of growth hormone secretagogue developed from Met-enkephalin led to reveal the endogenous ligand ghrelin and the receptors. Subsequently, many peptides, small molecules and peptidomimetics focusing on the ghrelin receptor, GHS-R1a, were derived. In this review, the key features of ghrelin's structure, forms, its bio-physiological functions, pathological roles and therapeutic potential have been highlighted. A few peptidomimetics and pseudo peptide synthetic perspectives have also been discussed to make ghrelin receptor ligands, clinical trials and their success.
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Affiliation(s)
- Syed Nasir Abbas Bukhari
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 2014, Saudi Arabia.
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15
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Abstract
Gastroparesis is characterized by symptoms suggestive of, and objective evidence of, delayed gastric emptying in the absence of mechanical obstruction. This review addresses the normal emptying of solids and liquids from the stomach and details the myogenic and neuromuscular control mechanisms, including the specialized function of the pyloric sphincter, that result in normal emptying, based predominantly on animal research. A clear understanding of fundamental mechanisms is necessary to comprehend derangements leading to gastroparesis, and additional research on human gastric muscles is needed. The section on pathophysiology of gastroparesis considers neuromuscular diseases that affect nonsphincteric gastric muscle, disorders of the extrinsic neural control, and pyloric dysfunction that lead to gastroparesis. The potential cellular basis for gastroparesis is attributed to the effects of oxidative stress and inflammation, with increased pro-inflammatory and decreased resident macrophages, as observed in full-thickness biopsies from patients with gastroparesis. Predominant diagnostic tests involving measurements of gastric emptying, the use of a functional luminal imaging probe, and high-resolution antral duodenal manometry in characterizing the abnormal motor functions at the gastroduodenal junction are discussed. Management is based on supporting nutrition; dietary interventions, including the physical reduction in particle size of solid foods; pharmacological agents, including prokinetics and anti-emetics; and interventions such as gastric electrical stimulation and pyloromyotomy. These are discussed briefly, and comment is added on the potential for individualized treatments in the future, based on optimal gastric emptying measurement and objective documentation of the underlying pathophysiology causing the gastroparesis.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Kenton M. Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV
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16
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Liu H, Sun D, Myasnikov A, Damian M, Baneres JL, Sun J, Zhang C. Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren. Nat Commun 2021; 12:6410. [PMID: 34737341 PMCID: PMC8568970 DOI: 10.1038/s41467-021-26735-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/14/2021] [Indexed: 12/26/2022] Open
Abstract
The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-Gi signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the Gi and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs.
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Affiliation(s)
- Heng Liu
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Dapeng Sun
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Alexander Myasnikov
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38120, USA
| | - Marjorie Damian
- Institut des Biomolécules Max Mousseron, CNRS, Université de Montpellier, ENSCM, Montpellier, France
| | - Jean-Louis Baneres
- Institut des Biomolécules Max Mousseron, CNRS, Université de Montpellier, ENSCM, Montpellier, France
| | - Ji Sun
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, 38120, USA.
| | - Cheng Zhang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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17
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Zheng T, Camilleri M. Management of Gastroparesis. Gastroenterol Hepatol (N Y) 2021; 17:515-525. [PMID: 35466306 PMCID: PMC9021159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Gastroparesis is a gastrointestinal motility disorder characterized by nausea, vomiting, early satiation, postprandial fullness, bloating, and upper abdominal pain. The diagnosis requires documented delay in gastric emptying with an optimal test such as scintigraphy or stable isotope gastric emptying breath test in the absence of mechanical obstruction. The pathophysiologic mechanisms of gastroparesis are multifactorial, including antroduodenal hypomotility, pylorospasm, impaired gastric accommodation, and visceral hypersensitivity. The etiologies of gastroparesis are broad, but the most common subtypes are idiopathic, diabetic, and postsurgical. Less frequent etiologies are neurodegenerative disorder (Parkinson disease), myopathies (scleroderma, amyloidosis), and neoplastic syndrome. Symptoms of gastroparesis can be refractory and challenging to manage, leading to reduced quality of life and significant health care expenditure. This article introduces the epidemiology, clinical presentation, diagnosis, and differential diagnoses of gastroparesis, followed by a focused discussion on its management, including nutritional support, prokinetic and antiemetic agents, and emerging interventions directed at the pylorus. Robust sham-controlled trials are needed to evaluate the long-term efficacy of gastric peroral endoscopic myotomy. A multidisciplinary approach with individualized strategies based on characterization of the patho-physiology is deemed necessary to enhance clinical outcomes.
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Affiliation(s)
- Ting Zheng
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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18
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Camilleri M, Atieh J. New Developments in Prokinetic Therapy for Gastric Motility Disorders. Front Pharmacol 2021; 12:711500. [PMID: 34504426 PMCID: PMC8421525 DOI: 10.3389/fphar.2021.711500] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/10/2021] [Indexed: 12/13/2022] Open
Abstract
Prokinetic agents amplify and coordinate the gastrointestinal muscular contractions to facilitate the transit of intra-luminal content. Following the institution of dietary recommendations, prokinetics are the first medications whose goal is to improve gastric emptying and relieve symptoms of gastroparesis. The recommended use of metoclopramide, the only currently approved medication for gastroparesis in the United States, is for a duration of less than 3 months, due to the risk of reversible or irreversible extrapyramidal tremors. Domperidone, a dopamine D2 receptor antagonist, is available for prescription through the FDA's program for Expanded Access to Investigational Drugs. Macrolides are used off label and are associated with tachyphylaxis and variable duration of efficacy. Aprepitant relieves some symptoms of gastroparesis. There are newer agents in the pipeline targeting diverse gastric (fundic, antral and pyloric) motor functions, including novel serotonergic 5-HT4 agonists, dopaminergic D2/3 antagonists, neurokinin NK1 antagonists, and ghrelin agonist. Novel targets with potential to improve gastric motor functions include the pylorus, macrophage/inflammatory function, oxidative stress, and neurogenesis. In the current review, we discuss the use of pharmacological approaches with potential to enhance motor functions in the management of gastroparesis.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
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19
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Kuo B, Scimia C, Dukes G, Zhang W, Gupta S, Chen C, Chuang E, Camilleri M. Randomised clinical trial: safety, pharmacokinetics and pharmacodynamics of trazpiroben (TAK-906), a dopamine D 2 /D 3 receptor antagonist, in patients with gastroparesis. Aliment Pharmacol Ther 2021; 54:267-280. [PMID: 34148244 DOI: 10.1111/apt.16451] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/09/2021] [Accepted: 05/14/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Gastroparesis is a chronic gastric motility disorder. Dopamine D2 /D3 receptor antagonists metoclopramide and domperidone are current treatment options but are associated with central nervous system and cardiovascular safety concerns, respectively, precluding chronic use. Trazpiroben (TAK-906), a dopamine D2 /D3 receptor antagonist, is under development for chronic treatment of moderate-to-severe gastroparesis. Nonclinical data suggest trazpiroben will have D2 /D3 receptor antagonism comparable with metoclopramide or domperidone. AIMS To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on prolactin and gastric function) of twice-daily trazpiroben (5, 25 and 100 mg) in participants with gastroparesis. METHODS This phase 2a pilot study evaluated gastric emptying using the gastric emptying breath test, with metoclopramide as an internal control. Gastric accommodation and gastroparesis symptoms were assessed using the nutrient drink test and American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, respectively. RESULTS Overall, 51 participants were enrolled. Trazpiroben was well tolerated, demonstrating a favourable safety profile without cardiovascular or central nervous system adverse events. All trazpiroben doses were rapidly absorbed and eliminated (t1/2z 4-5 hours), and D2 /D3 receptor target engagement confirmed by increased serum prolactin (peaking at trazpiroben 25 mg). No effect on gastric emptying was demonstrated with trazpiroben or metoclopramide (P > 0.05), although benefits in volume-to-fullness were seen at trazpiroben 5 mg (P > 0.05) and 25 mg (88.5 vs -26.3 mL; P = 0.019), and nonsignificant numerical aggregate symptom score improvements were observed with trazpiroben 25 mg vs placebo (P = 0.182). CONCLUSIONS Trazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941.
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Affiliation(s)
- Braden Kuo
- Harvard School of Medicine, Boston, MA, USA
| | - Cecilia Scimia
- Takeda Pharmaceuticals International Co., Cambridge, MA, USA
| | - George Dukes
- Takeda Pharmaceuticals International Co., Cambridge, MA, USA
| | - Wenwen Zhang
- Takeda Pharmaceuticals International Co., Cambridge, MA, USA
| | - Saurabh Gupta
- Takeda Pharmaceuticals International Co., Cambridge, MA, USA
| | - Chunlin Chen
- Takeda Pharmaceuticals International Co., Cambridge, MA, USA
| | - Emil Chuang
- Takeda Pharmaceuticals International Co., Cambridge, MA, USA
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20
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Camilleri M, Chedid V. Actionable biomarkers: the key to resolving disorders of gastrointestinal function. Gut 2020; 69:1730-1737. [PMID: 32269066 DOI: 10.1136/gutjnl-2019-320325] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 02/12/2020] [Accepted: 02/15/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Michael Camilleri
- Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | - Victor Chedid
- Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
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21
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Hong SW, Chun J, Kim J, Lee J, Lee HJ, Chung H, Cho SJ, Im JP, Kim SG, Kim JS. Efficacy and Safety of Ghrelin Agonists in Patients with Diabetic Gastroparesis: A Systematic Review and Meta-Analysis. Gut Liver 2020; 14:589-600. [PMID: 31816671 PMCID: PMC7492501 DOI: 10.5009/gnl19103] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 09/20/2019] [Accepted: 09/22/2019] [Indexed: 12/15/2022] Open
Abstract
Background/Aims Ghrelin agonists are emerging prokinetic agents for treating gastroparesis. Although recent clinical trials have demonstrated their efficacy in patients with diabetic gastroparesis (DG), the impact of such agents on symptoms and gastric dysmotility remains unclear. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of ghrelin agonists in patients with DG. Methods A search of common electronic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) was preformed, using keyword combinations that referenced ghrelin and DG and retrieving all eligible randomized controlled trials (RCTs) of ghrelin agonists versus placebo in patients with DG. The primary outcome measure was the change in patient-reported overall gastroparesis symptom scores. Secondary outcomes included the change in gastric emptying time, specific symptoms related to gastroparesis, and adverse events. A random-effects model was applied to all study outcomes. Heterogeneity among studies was determined by the chi-square test and I2 statistics. Results We selected six RCTs of patients with DG (n=557) for meta-analysis. Ghrelin agonist administration (vs placebo) significantly improved overall gastroparesis symptoms (standardized mean difference, –0.34; 95% confidence interval, –0.56 to –0.13) and significantly improved symptoms related to gastroparesis, including nausea, vomiting, early satiety, and abdominal pain. Adverse events recorded for ghrelin agonists and placebo did not differ significantly. There was no significant heterogeneity among eligible studies. Conclusions Compared with placebo, ghrelin agonists are effective and well-tolerated for the treatment of DG.
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Affiliation(s)
- Seung Wook Hong
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jaeyoung Chun
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jihye Kim
- Department of Internal Medicine, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea
| | - Jooyoung Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Jung Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyunsoo Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Soo-Jeong Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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22
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Hasler WL. Editorial: a need for glucose monitoring on prokinetic treatment with a ghrelin agonist in diabetic gastroparesis? Aliment Pharmacol Ther 2020; 52:545-546. [PMID: 32656829 DOI: 10.1111/apt.15792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- William L Hasler
- Division of Gastroenterology and Hepatology, University of Michigan Health System, Ann Arbor, MI, USA
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23
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Abstract
Gastroparesis is characterized by delayed gastric emptying, with symptoms such as nausea, vomiting and abdominal pain, in the absence of mechanical obstruction. In most cases, it is idiopathic although diabetes mellitus is another leading cause. The physiology of gastric emptying is a complex process which is influenced by various inputs including the central nervous system, enteric nervous system and gut hormones. Developments in our understanding of gastroparesis have now demonstrated dysfunction in these systems, thus disrupting normal gastric emptying. Once mechanical obstruction is excluded, gastric scintigraphy remains the gold standard for diagnosis although wireless motility capsule and breath testing are alternative methods for diagnosis. Treatment for gastroparesis is challenging, and widely available therapies are often limited either by their poor evidence for efficacy or concerns over their long-term safety profile. Novel prokinetic agents have shown initial promise in clinical trials, and new endoscopic techniques such as gastric per-oral endoscopic myotomy are emerging. These new treatment modalities may provide an option in refractory gastroparesis with the adage of reduced morbidity compared to surgical treatments.
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Affiliation(s)
- A Sullivan
- Homerton University Hospital, London, UK
| | | | - A Ruban
- Department of Surgery and Cancer, Imperial College, London, UK.
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24
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Hedegaard MA, Holst B. The Complex Signaling Pathways of the Ghrelin Receptor. Endocrinology 2020; 161:5734640. [PMID: 32049280 DOI: 10.1210/endocr/bqaa020] [Citation(s) in RCA: 35] [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: 12/12/2019] [Accepted: 02/10/2020] [Indexed: 12/13/2022]
Abstract
The ghrelin receptor (GhrR) is known for its strong orexigenic effects in pharmacological doses and has long been considered as a promising target for the treatment of obesity. Several antagonists have been developed to decrease the orexigenic signaling, but none of these have been approved for the treatment of obesity because of adverse effects and lack of efficacy. Heterodimerization and biased signaling are important concepts for G-protein coupled receptor (GPCR) signaling, and the influence of these aspects on the GhrR may be important for feeding behavior and obesity. GhrR has been described to heterodimerize with other GPCRs, such as the dopamine receptors 1 and 2, leading to a modulation of the signaling properties of both dimerization partners. Another complicating factor of GhrR-mediated signaling is its ability to activate several different signaling pathways on ligand stimulation. Importantly, some ligands have shown to be "biased" or "functionally selective," implying that the ligand favors a particular signaling pathway. These unique signaling properties could have a sizeable impact on the physiological functions of the GhrR system. Importantly, heterodimerization may explain why the GhrR is expressed in areas of the brain that are difficult for peptide ligands to access. One possibility is that the purpose of GhrR expression is to modulate the function of other receptors in addition to merely being independently activated. We suggest that a deeper understanding of the signaling properties of the GhrR will facilitate future drug discovery in the areas of obesity and weight management.
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Affiliation(s)
- Morten Adler Hedegaard
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Birgitte Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
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25
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Asha MZ, Khalil SFH. Pharmacological Approaches to Diabetic Gastroparesis: A systematic review of randomised clinical trials. Sultan Qaboos Univ Med J 2019; 19:e291-e304. [PMID: 31897312 PMCID: PMC6930032 DOI: 10.18295/squmj.2019.19.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 07/10/2019] [Accepted: 07/26/2019] [Indexed: 02/07/2023] Open
Abstract
Pharmacological interventions of diabetic gastroparesis (DG) constitute an essential element of a patient’s management. This article aimed to systematically review the available pharmacological approaches of DG, including their efficacy and safety. A total of 24 randomised clinical trials (RCTs) that investigated the efficacy and/or safety of medications targeting DG symptoms were identified using several online databases. Their results revealed that metoclopramide was the only approved drug for accelerating gastric emptying and improving disease symptoms. However, this medication may have several adverse effects on the cardiovascular and nervous systems, which might be resolved with a new intranasal preparation. Acceptable alternatives are oral domperidone for patients without cardiovascular risk factors or intravenous erythromycin for hospitalised patients. Preliminary data indicated that relamorelin and prucalopride are novel candidates that have proven to be effective and safe. Future RCTs should be conducted based on unified guidelines using universal diagnostic modalities to reveal reliable and comprehensive outcomes.
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Affiliation(s)
- Mohammad Z Asha
- Department of Internal Medicine, Dr Mohamad Amine Zbeib Polyclinic, Doha, Qatar
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26
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The Role of Adipose Tissue in the Pathogenesis and Therapeutic Outcomes of Inflammatory Bowel Disease. Cells 2019; 8:cells8060628. [PMID: 31234447 PMCID: PMC6627060 DOI: 10.3390/cells8060628] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 06/16/2019] [Accepted: 06/18/2019] [Indexed: 02/06/2023] Open
Abstract
Though historically regarded as an inert energy store, adipose tissue is a complex endocrine organ, which is increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD). Accumulating evidence points to visceral adipose tissue and specifically to its mesenteric component, or “creeping fat” as impacting on the disease course through its immunomodulatory properties. On the one hand, mesenteric fat acts as a physical barrier to inflammation and is involved in controlling host immune response to translocation of gut bacteria. On the other hand, however, there exists a strong link between visceral fat and complicated course of the disease with unfavorable therapeutic outcomes. Furthermore, “creeping fat” appears to play different roles in different IBD phenotypes, with the greatest pathogenetic contribution probably to an ileal form of Crohn’s disease. In this review, we summarize and discuss the existing literature on the subject and identify high-priority areas for future research. It may be that a better understanding of the role of mesenteric fat in IBD will determine new therapeutic targets and translate into improved clinical outcomes.
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Chakraborty S, Halland M, Burton D, Desai A, Neja B, Low P, Singer W, Camilleri M, Zinsmeister AR, Bharucha AE. GI Dysfunctions in Diabetic Gastroenteropathy, Their Relationships With Symptoms, and Effects of a GLP-1 Antagonist. J Clin Endocrinol Metab 2019; 104:1967-1977. [PMID: 30358871 PMCID: PMC6467444 DOI: 10.1210/jc.2018-01623] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022]
Abstract
CONTEXT Delayed gastric emptying (GE) is common but often asymptomatic in diabetes. The relationship between symptoms, glycemia, and neurohormonal functions, including glucagonlike peptide 1 (GLP-1), are unclear. OBJECTIVES To assess whether GE disturbances, symptoms during a GE study, and symptoms during enteral lipid infusion explain daily symptoms and whether GLP-1 mediates symptoms during enteral lipid infusion. DESIGN In this randomized controlled trial, GE, enteral lipid infusion, gastrointestinal (GI) symptoms during these assessments, autonomic functions, glycosylated hemoglobin (HbA1c), and daily GI symptoms (2-week Gastroparesis Cardinal Symptom Index diary) were evaluated. During enteral lipid infusion, participants received the GLP-1 antagonist exendin 9-39 or placebo. SETTING Single tertiary referral center. PARTICIPANTS 24 healthy controls and 40 patients with diabetic gastroenteropathy. MAIN OUTCOME MEASURES GE, symptoms during enteral lipid infusion, and the effect of exendin 9-39 on the latter. RESULTS In patients, GE was normal (55%), delayed (33%), or rapid (12%). During lipid infusion, GI symptoms tended to be greater (P = 0.06) in patients with diabetes mellitus (DM) than controls; exendin 9-39 did not affect symptoms. The HbA1c was inversely correlated with the mean symptom score during the GE study (r = -0.46, P = 0.003) and lipid infusion (r = -0.47, P < 0.01). GE and symptoms during GE study accounted for 40% and 32%, respectively, of the variance in daily symptom severity and quality of life. CONCLUSIONS In DM gastroenteropathy, GE and symptoms during a GE study explain daily symptoms. Symptoms during enteral lipid infusion were borderline increased but not reduced by a GLP-1 antagonist.
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Affiliation(s)
| | - Magnus Halland
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Duane Burton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Anshuman Desai
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Bridget Neja
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Phillip Low
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | | | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Alan R Zinsmeister
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Adil E Bharucha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Vijayvargiya P, Camilleri M, Chedid V, Mandawat A, Erwin PJ, Murad MH. Effects of Promotility Agents on Gastric Emptying and Symptoms: A Systematic Review and Meta-analysis. Gastroenterology 2019; 156:1650-1660. [PMID: 30711628 DOI: 10.1053/j.gastro.2019.01.249] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Studies have reported a lack of association between improvements in gastric emptying (GE) and upper gastrointestinal (UGI) symptoms with promotility drugs. However, GE test methods were suboptimal in some studies. We assessed improvements in GE and UGI symptoms in patients given promotility agents in studies with optimal or moderate test methods (scintigraphy or breath test, solid meal, >2 hours duration) compared to studies with suboptimal GE test methods. METHODS With an expert librarian, we completed an extensive search of publications in the Ovid MEDLINE (1946 to present), EMBASE (1988 to January 2018), and EBM Reviews Cochrane Central Register of Controlled Trials, without restrictions on language or year. Two independent reviewers evaluated the following inclusion criteria: randomized, blinded, parallel, or crossover trials of 5HT4 agonists, D2 receptor antagonist, or ghrelin agonists; trials that measured change in GE (T1/2) or composite UGI symptoms; trials of patients with functional dyspepsia and gastroparesis; and trials of GE test methods. Standardized mean differences (units expressed as SD) were used to standardize symptom assessments that were not uniform across studies. Random effects model was used to analyze data and meta-regression was used to evaluate the association between change in GE and UGI symptoms. RESULTS Of 899 studies considered, 22 studies assessed change in GE; 23 evaluated UGI symptoms; and 14 evaluated GE and UGI symptoms. Promotility agents significantly accelerated GE (T1/2) in all studies (mean reduction in T1/2, 16.3 minutes; 95% confidence interval, -22.1 to -10.6 minutes) and in studies that used optimal GE test methods (mean reduction in T1/2, 23.6 minutes; 95% confidence interval, -32.3 to -14.9 minutes). Promotility agents also significantly reduced UGI symptoms (mean reduction, 0.25 SD; 95% confidence interval, -0.37 to -0.13 SD). Meta-regression found no significant association between change in GE and UGI symptoms. However, when only studies with optimal GE test methods were evaluated, there was a significant positive association between improvement in GE and UGI symptoms (P = .02). CONCLUSIONS In a meta-analysis of published trials, we found promotility agents to significantly accelerate GE (when optimal test methods were used) and to produce significant improvements in UGI symptoms.
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Affiliation(s)
- Priya Vijayvargiya
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
| | - Victor Chedid
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota
| | - Aditya Mandawat
- Department of Cardiology, Duke University, Durham, North Carolina
| | | | - M Hassan Murad
- Evidence Based Practice Center, Mayo Clinic, Rochester, Minnesota
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Revicki DA, Speck RM, Lavoie S, Puelles J, Kuo B, Camilleri M, Almansa C, Parkman HP. The American neurogastroenterology and motility society gastroparesis cardinal symptom index-daily diary (ANMS GCSI-DD): Psychometric evaluation in patients with idiopathic or diabetic gastroparesis. Neurogastroenterol Motil 2019; 31:e13553. [PMID: 30734412 DOI: 10.1111/nmo.13553] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 12/07/2018] [Accepted: 12/22/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND The purpose of this study was to evaluate the measurement properties of the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, a patient-reported outcome instrument developed to meet US FDA recommendations for a symptom-based clinical trial endpoint in gastroparesis. The ANMS GCSI-DD assesses nausea, early satiety, postprandial fullness, and upper abdominal pain on a severity score from none (0) to very severe (4) and number of vomiting episodes during the past 24 hours. The composite score includes the first four symptoms, the core symptom score includes all five symptoms. METHODS Seventy-one patients diagnosed with idiopathic or diabetic gastroparesis were recruited for a four-week observational study. Patients completed the ANMS GCSI-DD at home between Baseline and Week 4. Statistical analyses included confirmatory factor analysis, item response theory analysis, internal consistency, test-retest reliability, and construct and known-groups validity. KEY RESULTS Unidimensionality for the composite and core symptom scores was supported, and items exhibited good fit. Internal consistency (Cronbach's alpha =0.85 and 0.83) and test-retest reliability were 0.89 and 0.88, for composite and core symptom scores, respectively. Convergent validity was supported by strong correlations with patient-reported and clinician measures. Baseline and Week 4 scores differed for three measures used to define disease severity status (P < 0.0001), supporting known-groups validity. CONCLUSIONS & INFERENCES The ANMS GCSI-DD has excellent reliability and validity, supporting its use to assess symptom-based endpoints in gastroparesis clinical studies. Further analyses will be conducted using clinical trial data to ascertain treatment responsiveness and define a responder.
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Affiliation(s)
| | | | | | | | - Braden Kuo
- Massachusetts General Hospital, Boston, Massachusetts
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Abstract
PURPOSE OF REVIEW This review examines the hormonal regulation of gastric emptying, a topic of increasing relevance, given the fact that medications that are analogs of some of these hormones or act as agonists at the hormonal receptors, are used in clinical practice for optimizing metabolic control in the treatment of type 2 diabetes and in obesity. RECENT FINDINGS The major effects on gastric emptying result from actions of incretins, particularly gastric inhibitory polypeptide, glucagon-like peptide-1, and peptide tyrosine-tyrosine, the duodenal and pancreatic hormones, motilin, glucagon, and amylin, and the gastric orexigenic hormones, ghrelin and motilin. All of these hormones delay gastric emptying, except for ghrelin and motilin which accelerate gastric emptying. These effects on gastric emptying parallel the effects of the hormones on satiation (by those retarding emptying) and increase appetite by those that accelerate emptying. Indeed, in addition to the effects of these hormones on hypothalamic appetite centers and glycemic control, there is evidence that some of their biological effects are mediated through actions on the stomach, particularly with the glucagon-like peptide-1 analogs or agonists used in treating obesity. SUMMARY Effects of gastrointestinal hormones on gastric emptying are increasingly recognized as important mediators of satiation and postprandial glycemic control.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA
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Revicki DA, Lavoie S, Speck RM, Puelles J, Kuo B, Camilleri M, Almansa C, Parkman HP. The content validity of the ANMS GCSI-DD in patients with idiopathic or diabetic gastroparesis. J Patient Rep Outcomes 2018; 2:61. [PMID: 30547386 PMCID: PMC6292831 DOI: 10.1186/s41687-018-0081-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/31/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) was developed to meet Food and Drug Administration (FDA) recommendations for patient-reported outcome (PRO) endpoints in gastroparesis studies, including therapeutic trials. The current version of the ANMS GCSI-DD contains five items pertaining to nausea, early satiety, post-prandial fullness, upper abdominal pain, and vomiting. The specific aims of this study were to determine if the appropriate symptoms are included in the ANMS GCSI-DD and to assess the content validity in patients with idiopathic (IG) and diabetic gastroparesis (DG). METHODS Patients diagnosed with IG or DG were recruited by five clinical sites in the United States for a cross-sectional, qualitative study involving one-on-one in-person concept elicitation and cognitive debriefing interviews. Concept elicitation included open-ended questions to elicit patients' symptoms and impacts of gastroparesis, while cognitive debriefing was designed to assess the comprehensiveness of the ANMS GCSI-DD and clarity of the instructions, items, and response scales. The interviews were audio-recorded and transcribed. Transcripts were analyzed using a content analysis approach with ATLAS.ti. RESULTS Of 25 patients interviewed, 15 (60%) had IG and 10 (40%) DG. Mean age of the sample was 42.3 years (range: 20-70 years), and most patients were female (n = 19, 76%) and white (n = 19, 76%). During concept elicitation, patients endorsed the following signs and symptoms as relevant and important to their condition: early satiety (n = 25, 100%), post-prandial fullness (n = 25, 100%), nausea (n = 22, 88%), upper abdominal pain (n = 18, 72%), vomiting (n = 15, 60%), and bloating (n = 11, 44%). Many patients (n = 20, 80%) experienced day-to-day symptom change. During cognitive debriefing, patients confirmed the ANMS GCSI-DD content was comprehensive and reflective of their gastroparesis experience. Patients could easily select a response option and describe how they arrived at their answers. Overall, patients found the instrument's instructions, recall period, items, and response options clear and understandable. CONCLUSIONS The ANMS GCSI-DD was easily understood, found to contain the most important symptoms for patients with IG and DG, and no changes were recommended. Results support the content validity of the ANMS GCSI-DD for clinical trials and clinical care among IG or DG patients.
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Affiliation(s)
| | - Sara Lavoie
- Evidera, 7101 Wisconsin Avenue, Suite 1400, Bethesda, MD 20814 USA
| | - Rebecca M. Speck
- Evidera, 7101 Wisconsin Avenue, Suite 1400, Bethesda, MD 20814 USA
| | - Jorge Puelles
- Takeda Pharmaceuticals, 61 Aldwych, London, WC2B 4AE UK
| | - Braden Kuo
- Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 USA
| | | | - Cristina Almansa
- Takeda Pharmaceuticals, 35 Lansdowne Street, Cambridge, MA 02139 USA
| | - Henry P. Parkman
- Temple University Hospital, 3401 N Broad Street, #1003, Philadelphia, PA 19140 USA
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Camilleri M, Chedid V, Ford AC, Haruma K, Horowitz M, Jones KL, Low PA, Park SY, Parkman HP, Stanghellini V. Gastroparesis. Nat Rev Dis Primers 2018; 4:41. [PMID: 30385743 DOI: 10.1038/s41572-018-0038-z] [Citation(s) in RCA: 231] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastroparesis is a disorder characterized by delayed gastric emptying of solid food in the absence of a mechanical obstruction of the stomach, resulting in the cardinal symptoms of early satiety, postprandial fullness, nausea, vomiting, belching and bloating. Gastroparesis is now recognized as part of a broader spectrum of gastric neuromuscular dysfunction that includes impaired gastric accommodation. The overlap between upper gastrointestinal symptoms makes the distinction between gastroparesis and other disorders, such as functional dyspepsia, challenging. Thus, a confirmed diagnosis of gastroparesis requires measurement of delayed gastric emptying via an appropriate test, such as gastric scintigraphy or breath testing. Gastroparesis can have idiopathic, diabetic, iatrogenic, post-surgical or post-viral aetiologies. The management of gastroparesis involves: correcting fluid, electrolyte and nutritional deficiencies; identifying and treating the cause of delayed gastric emptying (for example, diabetes mellitus); and suppressing or eliminating symptoms with pharmacological agents as first-line therapies. Several novel pharmacologic agents and interventions are currently in the pipeline and show promise to help tailor individualized therapy for patients with gastroparesis.
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Affiliation(s)
- Michael Camilleri
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
| | - Victor Chedid
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Alexander C Ford
- Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK
- Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
| | - Ken Haruma
- Department of Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Japan
| | - Michael Horowitz
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Karen L Jones
- National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, South Australia, Australia
| | - Phillip A Low
- Department of Neurology, Mayo Clinic, Rochester, MN, USA
| | - Seon-Young Park
- Division of Gastroenterology, Chonnam National University School of Medicine, Gwangju, Republic of Korea
| | - Henry P Parkman
- GI Section, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA
| | - Vincenzo Stanghellini
- Department of Digestive Diseases, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy
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Avalos DJ, Sarosiek I, Loganathan P, McCallum RW. Diabetic gastroparesis: current challenges and future prospects. Clin Exp Gastroenterol 2018; 11:347-363. [PMID: 30310300 PMCID: PMC6165730 DOI: 10.2147/ceg.s131650] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Diabetic gastroparesis (DMGP) is a condition of delayed gastric emptying after gastric outlet obstruction has been excluded. Symptoms of nausea, vomiting, early satiety, bloating, and abdominal pain are associated with DMGP. Uncontrolled symptoms can lead to overall poor quality of life and financial burdens on the healthcare system. A combination of antiemetics and prokinetics is used in symptom control; metoclopramide is the main prokinetic available for clinical use and is the only U.S. Food and Drug Administration-approved agent in the United States. However, a black box warning in 2009 reporting its association with tardive dyskinesia and recommending caution in chronically using this agent beyond 3 months has decreased its role in clinical practice. There is an unmet need for new prokinetics with good efficacy and safety profiles. Currently, there are several new drugs with different mechanisms of action in the pipeline that are under investigation and show promising preliminary results. Surgically combining gastric electrical stimulation with pyloroplasty is considered "gold" standard. Advances in therapeutic endoscopic intervention with gastric per-oral endoscopic pyloromyotomy have also been shown to improve gastric emptying and gastroparesis (GP) symptoms. In this review, we will comment on the challenges encountered when managing patients with DMGP and provide an update on advances in drug development and endoscopic and surgical interventions.
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Affiliation(s)
- Danny J Avalos
- Division of Gastroenterology, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, El Paso, TX, USA,
| | - Irene Sarosiek
- Division of Gastroenterology, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, El Paso, TX, USA,
| | - Priyadarshini Loganathan
- Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Richard W McCallum
- Division of Gastroenterology, Center for Neurogastroenterology and GI Motility, Texas Tech University Health Sciences Center, El Paso, TX, USA,
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Abstract
This article is a comprehensive review of diabetic gastroparesis, defined as delayed or disordered gastric emptying, including basic principles and current trends in management. This review includes sections on anatomy and physiology, diagnosis and differential diagnosis as well as management and current guidelines for treatment of diabetic gastroparesis. Diabetic gastroparesis (DGp) is a component of autonomic neuropathy resulting from long-standing poorly controlled type 1 and type 2 diabetes. The diagnostic workup of DGp first excludes obstruction and other causes including medications that may mimic delayed/disordered gastric emptying. Targeting nutrition, hydration, symptomatic relief and glycemic control are mainstays of treatment for DGp. Additionally, optimal treatment of DGp includes good glycemic management, often involving customizing insulin delivery using basal-bolus insulin and technology, including sensor-augmented pumps and continuous glucose monitoring systems. Prokinetic medications may be helpful in DGp symptoms, although only limited number of medications is currently available in the USA. Selected medication-refractory patients with DGp may benefit from gastric neuromodulation, and some from surgical interventions including pyloric therapies that can also be done endoscopically. As is true of any of the diabetic complications, prevention of DGp by early and optimal glycemic control is more cost-effective.Funding: Hansa Medcell, India.
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Affiliation(s)
- Sathya Krishnasamy
- Division of Endocrinology, Metabolism, and Diabetes, University of Louisville, Louisville, KY, USA
| | - Thomas L Abell
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville, Louisville, KY, USA.
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Ma J, Vella A. What Has Bariatric Surgery Taught Us About the Role of the Upper Gastrointestinal Tract in the Regulation of Postprandial Glucose Metabolism? Front Endocrinol (Lausanne) 2018; 9:324. [PMID: 29997575 PMCID: PMC6028568 DOI: 10.3389/fendo.2018.00324] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Accepted: 05/31/2018] [Indexed: 02/06/2023] Open
Abstract
The interaction between the upper gastrointestinal tract and the endocrine system is important in the regulation of metabolism and of weight. The gastrointestinal tract has a heterogeneous cellular content and comprises a variety of cells that elaborate paracrine and endocrine mediators that collectively form the entero-endocrine system. The advent of therapy that utilizes these pathways as well as the association of bariatric surgery with diabetes remission has (re-)kindled interest in the role of the gastrointestinal tract in glucose homeostasis. In this review, we will use the changes wrought by bariatric surgery to provide insights into the various gut-pancreas interactions that maintain weight, regulate satiety, and limit glucose excursions after meal ingestion.
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Affiliation(s)
- Jing Ma
- Division of Endocrinology and Metabolism, Shanghai Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, NY, United States
| | - Adrian Vella
- Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, NY, United States
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Lacy BE, Parkman HP, Camilleri M. Chronic nausea and vomiting: evaluation and treatment. Am J Gastroenterol 2018; 113:647-659. [PMID: 29545633 DOI: 10.1038/s41395-018-0039-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 02/05/2018] [Indexed: 12/11/2022]
Abstract
Nausea is an uneasy feeling in the stomach while vomiting refers to the forceful expulsion of gastric contents. Chronic nausea and vomiting represent a diverse array of disorders defined by 4 weeks or more of symptoms. Chronic nausea and vomiting result from a variety of pathophysiological processes, involving gastrointestinal and non-gastrointestinal causes. The prevalence of chronic nausea and vomiting is unclear, although the epidemiology of specific conditions, such as gastroparesis and cyclic vomiting syndrome, is better understood. The economic impact of chronic nausea and vomiting and effects on quality of life are substantial. The initial diagnostic evaluation involves distinguishing gastrointestinal causes of chronic nausea and vomiting (e.g., gastroparesis, cyclic vomiting syndrome) from non-gastrointestinal causes (e.g., medications, vestibular, and neurologic disorders). After excluding anatomic, mechanical and biochemical causes of chronic nausea and vomiting, gastrointestinal causes can be grouped into two broad categories based on the finding of delayed, or normal, gastric emptying. Non-gastrointestinal disorders can also cause chronic nausea and vomiting. As a validated treatment algorithm for chronic nausea and vomiting does not exist, treatment should be based on a thoughtful discussion of benefits, side effects, and costs. The objective of this monograph is to review the evaluation and treatment of patients with chronic nausea and vomiting, emphasizing common gastrointestinal causes.
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Affiliation(s)
- Brian E Lacy
- Mayo Clinic, Jacksonville, FL, USA. Temple University, Philadelphia, PA, USA. Mayo Clinic, Rochester, MN, USA
| | - Henry P Parkman
- Mayo Clinic, Jacksonville, FL, USA. Temple University, Philadelphia, PA, USA. Mayo Clinic, Rochester, MN, USA
| | - Michael Camilleri
- Mayo Clinic, Jacksonville, FL, USA. Temple University, Philadelphia, PA, USA. Mayo Clinic, Rochester, MN, USA
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Camilleri M, McCallum RW, Tack J, Spence SC, Gottesdiener K, Fiedorek FT. Efficacy and Safety of Relamorelin in Diabetics With Symptoms of Gastroparesis: A Randomized, Placebo-Controlled Study. Gastroenterology 2017; 153:1240-1250.e2. [PMID: 28760384 PMCID: PMC5670003 DOI: 10.1053/j.gastro.2017.07.035] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/24/2017] [Accepted: 07/25/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Gastroparesis is a complication of diabetes with few treatment options. Relamorelin (also referred to as RM-131) is a selective, prokinetic agonist of ghrelin. We aimed to evaluate the efficacy of relamorelin on symptoms and gastric emptying (GE) in a 12-week, phase 2B study of diabetic patients with moderate to severe gastroparesis symptoms (DG). METHODS We performed a study of 393 patients with DG (37.7% male; 9.9% with type 1 diabetes; median age, 58.2 years [range 20-76]; median body mass index, 31.4 kg/m2 [range, 18.2-60.1]; HbA1c level, 7.6%, [range, 5.2-11.0]). All participants had 13C-spirulina GE breath test T1/2 values of 79 minutes or more (with 89.8% delayed relative to 90th %ile of normal, 85.75 minutes), recent vomiting, and gastroparesis cardinal symptom index-daily diary scores of 2.6 or more. Patients were randomly assigned to groups given placebo (n=104) or relamorelin (10 μg [n=98], 30 μg [n=109], or 100 μg [n=82] twice daily) for 12 weeks, following a 2-week, single-blind, placebo run-in period. Patient-reported outcomes were determined from DG Symptom Severity daily e-diaries, in which patients recorded vomiting frequency and symptom scores (nausea, abdominal pain, postprandial fullness, and bloating) on a 0-10 scale. Endpoints were change from baseline in vomiting frequency, composite DG Symptom Severity score, GE, and safety. We performed longitudinal, mixed-effects model analysis using repeated measures, with baseline and baseline-by-week interaction values as covariates. RESULTS Patients given relamorelin had a 75% reduction in vomiting frequency compared with baseline, but this difference was not significant compared with the placebo group. All 4 symptoms of DG (composite or individual symptoms) were significantly reduced over the 12-week study period in all 3 relamorelin dose groups compared with the placebo group (all P < .05, based on longitudinal analysis over 12 weeks). Relamorelin significantly accelerated GE from baseline compared with placebo (by 12%, P < .05 for the 10 μg and 30 μg groups; P = .051 for the 100 μg group). Dose-related worsening of glycemic control was noted in 14.5% of patients who received relamorelin; some required insulin or other diabetes drug dosage adjustments. CONCLUSIONS In a phase 2B randomized trial of patients with moderate to severe DG, relamorelin significantly reduced core symptoms of DG and overall composite score compared with placebo, accelerated GE, and was generally safe and well tolerated. ClinicalTrials.gov Identifier: NCT02357420.
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Affiliation(s)
| | - Richard W McCallum
- Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, Texas
| | - Jan Tack
- University Hospital, Leuven, Belgium
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Abstract
OPINION STATEMENT Diabetes mellitus (DM) and its associated complications are becoming increasingly prevalent. Gastrointestinal symptoms associated with diabetes is known as diabetic enteropathy (DE) and may manifest as either diarrhea, fecal incontinence, constipation, dyspepsia, nausea, and vomiting or a combination of symptoms. The long-held belief that vagal autonomic neuropathy is the primary cause of DE has recently been challenged by newer theories of disease development. Specifically, hyperglycemia and the resulting oxidative stress on neural networks, including the nitrergic neurons and interstitial cells of Cajal (ICC), are now believed to play a central role in the development of DE. DE occurs in the majority of patients with diabetes; however, tools for early diagnosis and targeted therapy to counter the detrimental and potentially irreversible effects on the small bowel are lacking. Delay in diagnosis is further compounded by the fact that DE symptoms overlap with those of gastroparesis or can be confused with side effects from diabetes medications. Still, early recognition of the presence of DE is essential to mitigating symptoms and preventing further progression of complications including dysmotility and malabsorption. Current diagnostic modalities include manometry, wireless motility capsule (SmartPill™), and scintigraphy; however, these are not regularly utilized in clinical practice due to limited availability. Several medications are available for symptom relief in DE patients including rifaximin for small intestinal bacterial overgrowth (SIBO) and somatostatin analogues for diarrhea. While rodent models on stem cell therapy and alteration of the microbiome are promising, there is still a great need for further research on the pathologic underpinnings and development of novel treatment modalities for DE.
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Affiliation(s)
- Jonathan Gotfried
- Temple University Digestive Disease Center, Temple University Hospital, Philadelphia, PA, USA
| | - Stephen Priest
- Temple University Lewis Katz School of Medicine at Temple University & Temple University Health System, Philadelphia, PA, USA
| | - Ron Schey
- Temple University Digestive Disease Center, Temple University Hospital, Philadelphia, PA, USA. .,Temple University Lewis Katz School of Medicine at Temple University & Temple University Health System, Philadelphia, PA, USA.
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Abstract
PURPOSE OF REVIEW The goal of this review is to review the current status of prokinetics and to place it in historical context. Impaired motility and thus propulsion have long been thought to play important roles in the pathogenesis of a number of gastrointestinal disorders including gastroesophageal reflux disease (GERD), gastroparesis, chronic idiopathic pseudo-obstruction, and constipation. Historically, disordered motility was also thought to contribute to a number of functional gastrointestinal disorders such as functional dyspepsia (FD) and irritable bowel syndrome (IBS). RECENT FINDINGS As we learn more of the pathophysiology of FD, IBS, GERD, constipation, and gastroparesis, the limitations of a therapeutic strategy based on the stimulation of motility (i.e., the use of a prokinetic) have become apparent and the disappointments of the past explained. The development of prokinetic drugs has also been hampered by the non-selective nature of many of the agents studied to date which resulted in some unexpected side effects. There is still an unmet need for an effective and safe prokinetic, but drug development in this area must be mindful of the challenges of the area and the need for selectivity for a given target receptor.
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Affiliation(s)
- Eamonn M M Quigley
- Lynda K and David M Underwood Center for Digestive Disorders, Houston, TX, USA.
- Division of Gastroenterology and Hepatology, The Methodist Hospital, 6550 Fannin St, SM 1201, Houston, TX, 77030, USA.
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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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Chedid V, Camilleri M. Relamorelin for the treatment of gastrointestinal motility disorders. Expert Opin Investig Drugs 2017; 26:1189-1197. [PMID: 28847163 DOI: 10.1080/13543784.2017.1373088] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Current treatments for gastroparesis are limited. Chronic idiopathic constipation (CIC) has more treatment options, but none are efficacious for severe cases. Areas covered: Molecular targets to accelerate GI motility are being identified, and relamorelin, a synthetic ghrelin analog, has been promising. In humans, relamorelin increases growth hormone levels and accelerates gastric emptying. Relamorelin was superior to placebo for symptom relief in phase IIA studies for diabetic gastroparesis (DG) and CIC. In phase IIB studies in DG, relamorelin did not significantly reduce vomiting frequency when compared to placebo, but it reduced four symptoms of DG (nausea, fullness, bloating and abdominal pain) and accelerated gastric emptying. To date, relamorelin has been well tolerated and safe in humans without cardiac or neurologic adverse effects. It is still in clinical trial stages and not yet approved by the Food and Drug Administration. Phase III studies are underway. Expert opinion: Relamorelin shows promise in treating DG, with a reduction in core symptoms. Relative to available treatments, it appears to be efficacious and well tolerated. The absence of neurological or cardiovascular adverse effects places it at an advantage over other available therapies. Once approved, it will likely become the drug of first choice for DG.
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Affiliation(s)
- Victor Chedid
- a Department of Medicine, Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
| | - Michael Camilleri
- a Department of Medicine, Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA
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Effect of Intravenous Fluids and Analgesia on Dysmotility in Patients With Acute Pancreatitis: A Prospective Cohort Study. Pancreas 2017; 46:858-866. [PMID: 28697124 DOI: 10.1097/mpa.0000000000000864] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Analgesia and intravenous fluid resuscitation are cornerstones of initial patient management in acute pancreatitis (AP). The aim was to investigate the effect of intravenous fluids and analgesia on gastrointestinal motility in the early course of AP. METHODS Gastrointestinal dysmotility was assessed using the Gastroparesis Cardinal Symptom Index (GCSI). One-way analysis of variance and analysis of covariance were conducted, adjusting for age, sex, body mass index, severity of AP, preexisting diabetes mellitus, and time from first symptom onset to hospital admission. RESULTS A total of 108 patients with AP were prospectively enrolled. Opioid analgesia, when compared with nonopioid analgesia, was significantly associated with increase in total GCSI score in both unadjusted and adjusted analyses. There was no significant difference between aggressive and nonaggressive fluid resuscitation in both unadjusted and adjusted analyses. A combination of opioids and any intravenous fluids was associated with a significantly increased total GCSI score compared with opioids and no intravenous fluids in both unadjusted and adjusted analyses. Duration of symptoms was the confounder that significantly affected 6 of 9 studied associations. CONCLUSIONS Intravenous fluids and analgesia significantly affect motility independent of severity and other covariates. Guidelines on prudent use of opioids and fluids in AP need to be developed, particularly taking into account duration of symptoms from onset to hospitalization.
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Mosińska P, Zatorski H, Storr M, Fichna J. Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists. J Neurogastroenterol Motil 2017; 23:171-179. [PMID: 28238253 PMCID: PMC5383112 DOI: 10.5056/jnm16183] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/19/2016] [Accepted: 01/08/2017] [Indexed: 12/22/2022] Open
Abstract
There is an unmet need for effective pharmacological therapies for constipation, a symptom that significantly deteriorates patients’ quality of life and impacts health care. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and has been shown to exert prokinetic effects on gastrointestinal (GI) motility via the vagus and pelvic nerves. The pharmacological potential of ghrelin is hampered by its short half-life. Ghrelin receptor (GRLN-R) agonists with enhanced pharmacokinetics were thus developed. Centrally penetrant GRLN-R agonists stimulate defecation and improve impaired lower GI transit in animals and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other GRLN-R analogs which are in preclinical or clinical stages of development for the management of disorders with underlying GI hypomotility, like constipation.
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Affiliation(s)
- Paula Mosińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Hubert Zatorski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Martin Storr
- Center of Endoscopy, Starnberg, Germany and Walter-Brendel-Centre, Ludwig-Maximilians University Munich, Munich, Germany
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Sanger GJ, Pasricha PJ. Investigational drug therapies for the treatment of gastroparesis. Expert Opin Investig Drugs 2017; 26:331-342. [PMID: 28127997 DOI: 10.1080/13543784.2017.1288214] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Gastroparesis is defined by nausea, vomiting, pain, early satiety and bloating, and characterized by delayed gastric emptying without obvious structural abnormalities. Metoclopramide is widely used, increasing gastric emptying and inhibiting nausea and vomiting. Other drugs are available in certain countries and some are used 'off-label' because they increase gastric emptying or inhibit emesis. However, correlation between gastroparesis symptoms and rates of gastric emptying is poor. For anti-emetic drugs, dose-ranging and Phase III trials in gastroparesis are lacking. Areas covered: Gastric motility may still be disordered, leading to nausea, even though gastric emptying is unchanged. One hypothesis is that interstitial cells of Cajal (ICC) are damaged by diabetes leading to gastric dysrhythmia and nausea. Novel approaches to treatment of nausea also include the use of ghrelin receptor agonists, highlighting a link between appetite and nausea. Expert opinion: There is an urgent need to diversify away from historical drug targets. In particular, there is a need to control nausea by regulating ICC functions and/or by facilitating appetite via ghrelin receptor agonists. It is also important to note that different upper gastrointestinal disorders (gastroparesis, chronic unexplained nausea and vomiting, functional dyspepsia) are difficult to distinguish apart, suggesting wider therapeutic opportunity.
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Affiliation(s)
- Gareth J Sanger
- a Professor of Neuropharmacology , Blizard Institute and the National Centre for Bowel Research, Barts The London School of Medicine and Dentistry, Queen Mary University of London , London , UK
| | - Pankaj Jay Pasricha
- b Vice Chair of Medicine for Innovation and Commercialization , Johns Hopkins University School of Medicine, Director, Johns Hopkins Center for Neurogastroenterology, Professor of Medicine and Neurosciences, Professor of Innovation Management, Johns Hopkins Carey School of Business , Baltimore , MD , USA
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Stievenard A, Méquinion M, Andrews ZB, Destée A, Chartier-Harlin MC, Viltart O, Vanbesien-Mailliot CC. Is there a role for ghrelin in central dopaminergic systems? Focus on nigrostriatal and mesocorticolimbic pathways. Neurosci Biobehav Rev 2017; 73:255-275. [DOI: 10.1016/j.neubiorev.2016.11.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 11/23/2016] [Accepted: 11/25/2016] [Indexed: 12/21/2022]
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Parthasarathy G, Kudva YC, Low PA, Camilleri M, Basu A, Bharucha AE. Relationship Between Gastric Emptying and Diurnal Glycemic Control in Type 1 Diabetes Mellitus: A Randomized Trial. J Clin Endocrinol Metab 2017; 102:398-406. [PMID: 27880079 PMCID: PMC5413165 DOI: 10.1210/jc.2016-2809] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 11/22/2016] [Indexed: 12/13/2022]
Abstract
CONTEXT In type 1 diabetes (T1D), delayed gastric emptying (GE) may predispose to a mismatch between insulin delivery and glucose absorption. Previous studies evaluated, only partly, the relationship between delayed GE and postprandial, but not diurnal, glycemia. OBJECTIVE To assess the relationship between GE disturbances and glycemic control in T1D and the effects of accelerating GE on glycemic control. DESIGN, SETTING, AND PARTICIPANTS This was a randomized placebo-controlled trial in 30 patients with T1D on an insulin pump at an academic medical center. INTERVENTION(S) GE was evaluated with a [13C]-Spirulina breath test at baseline (GEbaseline), during intravenous saline or erythromycin (2 or 3 mg/kg; GEiv), and after 7 days of oral erythromycin or placebo (GEoral). Weighed meals were provided throughout the study. MAIN OUTCOME MEASURE(S) These were GE and continuous glucose monitoring (CGM). RESULTS The baseline glycosylated hemoglobin was 7.6% ± 0.8% (60 ± 8.7 mmol/mol); 12 patients (40%) had delayed GE; faster GE was associated with a greater postprandial CGM-based glucose, but slower GE was not associated with postprandial hypoglycemia (<70 mg/dL). Intravenous (3 mg/kg) but not oral erythromycin accelerated GE. The relationship between GE and glycemia differed between the postprandial periods and the entire day. After adjusting for carbohydrate intake and insulin consumption, faster GE was associated with more hyperglycemia during the postprandial period but lower glucose values across the entire study. CONCLUSIONS In T1D, pharmacologically mediated acceleration of GE increases postprandial CGM-based glucose. In contrast, delayed GE is associated with greater CGM-based glucose values over the entire day.
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Affiliation(s)
| | - Yogish C. Kudva
- Division of Endocrinology, Department of Internal Medicine, and
| | - Phillip A. Low
- Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905
| | | | - Ananda Basu
- Division of Endocrinology, Department of Internal Medicine, and
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From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation. Int J Mol Sci 2017; 18:ijms18020273. [PMID: 28134808 PMCID: PMC5343809 DOI: 10.3390/ijms18020273] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 01/19/2017] [Indexed: 12/20/2022] Open
Abstract
Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.
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Taddei RN, Spinnato F, Jenner P. New Symptomatic Treatments for the Management of Motor and Nonmotor Symptoms of Parkinson's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2017; 132:407-452. [DOI: 10.1016/bs.irn.2017.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Hasler WL. Newest Drugs for Chronic Unexplained Nausea and Vomiting. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2016; 14:371-385. [PMID: 27726068 PMCID: PMC5814321 DOI: 10.1007/s11938-016-0110-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OPINION STATEMENT Chronic unexplained nausea and vomiting (CUNV) refers to a symptom complex defined by nausea and/or vomiting with normal diagnostic testing, including anatomic assessments (including upper endoscopy) and measures of upper gut function (e.g., gastric emptying testing). Nausea and vomiting in this condition are postulated to result from aberrant peripheral or central neurohumoral activity. A substantial subset of patients satisfies this diagnosis as more than half of individuals referred for scintigraphic testing exhibit normal gastric emptying rates. No randomized, placebo-controlled trials of any medication treatment have been performed in CUNV. However, agents with potential therapeutic benefits in CUNV include antiemetic drugs, neuromodulatory treatments which are proposed to act by reducing gastric sensitivity, and medications with prokinetic action to stimulate upper gut propulsion. Recently approved drugs with antiemetic capability include serotonin antagonists with novel modes of delivery and neurokinin antagonists with or without additional serotonergic blocking capabilities. Existing neuroleptics and pain-modifying neuromodulatory therapies with fortuitous antiemetic benefits are being considered for their benefits in this disorder. Furthermore, current investigations will define potential therapeutic actions of agents that stimulate gastric emptying via action on gastroduodenal serotonin, motilin, and ghrelin receptors. This current research may broaden the treatment options for refractory cases of unexplained nausea and vomiting.
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Affiliation(s)
- William L Hasler
- Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, SPC 5362, Ann Arbor, MI, 48109, USA.
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50
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Nelson AD, Camilleri M, Acosta A, Busciglio I, Linker Nord S, Boldingh A, Rhoten D, Ryks M, Burton D. Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers. Neurogastroenterol Motil 2016; 28:1705-1713. [PMID: 27283792 PMCID: PMC5083171 DOI: 10.1111/nmo.12870] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 05/06/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND Synthetic human ghrelin accelerates gastric emptying, reduces gastric accommodation, and results in numerical increases in postprandial symptom scores. The ghrelin receptor agonist, relamorelin, accelerates gastric emptying in patients with diabetic gastroparesis. AIM To measure pharmacological effects of relamorelin on gastric accommodation, distal antral motility, and satiation in healthy volunteers. METHODS In a placebo-controlled, double-blind, randomized study of 16 healthy volunteers, we compared effects of 30 μg subcutaneous (s.c.) relamorelin to placebo on: (i) gastric volumes measured by single photon emission computed tomography, (ii) 1-h postprandial distal antral motility index (MI) by 15-lumen perfusion gastroduodenal manometry, and (iii) satiation tested by Ensure nutrient drink test. Primary endpoints were: fasting and postprandial gastric volumes, distal antral phasic pressure activity (number of contractions, mean amplitude, and MI), and maximum tolerated volume. Results were normally distributed and the two treatment groups were compared using t-test. KEY RESULTS Relamorelin, 30 μg s.c., significantly increased the number of contractions in the distal antrum during 0-60 min postmeal when compared to placebo (p = 0.022); this was also observed in the first two 15-min periods (p = 0.005 and 0.015 for number of contractions 0-15 and 16-30). There was borderline increase in MI0-15 (p = 0.055) and numerically increased MI0-60 (p = 0.139) and MI16-30 (p = 0.116). The amplitude of contractions was not significantly increased. Relamorelin did not significantly alter fasting or postprandial gastric volumes, gastric accommodation, or satiation volumes and symptoms. CONCLUSIONS & INFERENCES Relamorelin increases frequency of distal antral motility contractions without significant effects on amplitude of contractions. The lack of inhibition of accommodation and absence of increase in satiation symptoms support relamorelin for the treatment of symptomatic gastroparesis (ClinicalTrials.gov NCT02466711).
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Affiliation(s)
- A. D. Nelson
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - M. Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - A. Acosta
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - I. Busciglio
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - S. Linker Nord
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - A. Boldingh
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - D. Rhoten
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - M. Ryks
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
| | - D. Burton
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER); Mayo Clinic; Rochester MN USA
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