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Li W, Sha B, Bai H, Zhang T, Wang S, Ambedkar Kumar Y, Zhu Y, Yu L, Xu X. How to distinguish PPI-refractory from PPI-responsive patients in gastro-oesophageal reflux-induced chronic cough: post-reflux swallow induced peristaltic wave index and mean nocturnal baseline impedance provide new predictive factors. ERJ Open Res 2025; 11:00299-2024. [PMID: 39834600 PMCID: PMC11744322 DOI: 10.1183/23120541.00299-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/13/2024] [Indexed: 01/22/2025] Open
Abstract
Background The results of empirical trials with proton pump inhibitors (PPIs) for management of gastro-oesophageal reflux-induced chronic cough (GERC) have resulted in considerable controversy, and the mechanism of PPI refractoriness remains unclear. Our study aims to identify the predictors of PPI refractoriness of GERC in a retrospective clinical study. Methods In total, 128 GERC patients were enrolled between March 2018 and October 2022. Regression analysis was utilised to create a model for predicting PPI-refractory of GERC using retrospective analysis of the general data and MII-pH indicators. Results The post-reflux swallow induced peristaltic wave index (PSPWI) was lower in the PPI-refractory group than the PPI-responsive group (33.89±7.38 versus 39.45±9.47, respectively, p<0.001), as were the mean nocturnal baseline impedance (MNBI) and proximal MNBI (2092.11 (IQR: 652.23)] versus 2426.52 (IQR: 917.39) Ω, respectively, p=0.012; 1599.50 (IQR: 1206.63) versus 2274.50 (IQR: 1775.29) Ω, respectively, p=0.001). Multivariate logistic regression analysis identified the PSPWI (odds ratio 0.919, p=0.001) as an independent predictor of PPI-refractory GERC. Conclusions The diagnostic value of both proximal MNBI ≤39.90% and MNBI ≤2233.58 Ω had moderate sensitivity (71.67%) and specificity (75.00%) to identify PPI-refractory GERC.
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Affiliation(s)
- Wanzhen Li
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- W. Li, B. Sha and H. Bai contributed equally to this article as joint first authors
| | - Bingxian Sha
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- W. Li, B. Sha and H. Bai contributed equally to this article as joint first authors
| | - Haodong Bai
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- W. Li, B. Sha and H. Bai contributed equally to this article as joint first authors
| | - Tongyangzi Zhang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shengyuan Wang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yadav Ambedkar Kumar
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yiqing Zhu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Li Yu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- L. Yu and X. Yu contributed equally to this article as lead authors and supervised the work
| | - Xianghuai Xu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- L. Yu and X. Yu contributed equally to this article as lead authors and supervised the work
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Patel P, Layne S, Leiman DA. Regurgitation, eructation, and supragastric belch: retrograde esophageal motility, disorders, and treatment. Curr Opin Gastroenterol 2024; 40:442-448. [PMID: 39150445 DOI: 10.1097/mog.0000000000001059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
PURPOSE OF REVIEW This review describes pathologic conditions of retrograde flow into the esophagus along with recent therapeutic advances and treatment options. RECENT FINDINGS The esophagus facilitates anterograde and retrograde movement of contents, the latter of which is mediated by transient lower esophageal sphincter relaxations (TLESRs). Gastroesophageal reflux disease (GERD) often includes esophageal-specific symptoms such as heartburn or regurgitation. Volume regurgitation responds less frequently to acid suppression with proton pump inhibitors (PPIs) than heartburn, given its relationship with incompetence of the esophagogastric junction (EGJ) and increased frequency of TLESRs. Therefore, although the refluxate pH can be altered with PPIs, the frequency of reflux episodes is generally not reduced and surgical and endoscopic treatments may be favored. Other instances of abnormal retrograde esophageal flow respond better to medical therapy, or lifestyle interventions. Compared to gastric belching because of increased stomach distension, supragastric belching is caused by intake of air from pharynx into the esophagus followed by rapid expulsion of air. These conditions can be distinguished on esophageal tests such as high-resolution manometry and are likely to respond to behavioral modifications. SUMMARY Retrograde flow into the esophagus can be a normal occurrence, but diagnostic testing to distinguish causes can guide appropriate intervention.
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Affiliation(s)
- Pooja Patel
- Division of Gastroenterology, Duke University
| | | | - David A Leiman
- Division of Gastroenterology, Duke University
- Duke Clinical Research Institute, Durham, North Carolina, USA
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Sawada A, Sifrim D. How to recognize and treat rumination syndrome. Curr Opin Gastroenterol 2023; 39:340-346. [PMID: 37097822 DOI: 10.1097/mog.0000000000000937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
PURPOSE OF REVIEW Rumination syndrome (RS) is a functional gastroduodenal disorder characterized by repeated effortless regurgitation or vomiting of recently ingested food without retching. RS generally has been considered a rare entity. However, it has been increasingly recognized that many RS patients are likely to be underdiagnosed. This review discusses how to recognize and manage RS patients in clinical practice. RECENT FINDINGS A recent epidemiological study that included over 50,000 individuals found that the prevalence of RS around the world is 3.1%. In patients with proton pump inhibitor (PPI)-refractory reflux symptoms, postprandial high-resolution manometry combined with impedance (HRM/Z) reveals that RS accounts for up to 20% of those cases. HRM/Z can be a gold standard for objective RS diagnosis. In addition, off-PPI 24-h impedance pH monitoring can suggest the possibility of RS when it reveals frequent postprandial, non-acid reflux with a high symptom index. Modulated cognitive behavioral therapy (CBT) targeting secondary psychological maintaining mechanisms almost eliminates regurgitation. SUMMARY The prevalence of RS is higher than generally thought. For patients suspected of RS, HRM/Z is useful to distinguish RS from gastroesophageal reflux disease. CBT can be a highly effective therapeutic option.
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Affiliation(s)
- Akinari Sawada
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK
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Arabpour E, Khoshdel S, Akhgarzad A, Abdi M, Tabatabaie N, Alijanzadeh D, Abdehagh M. Baclofen as a therapeutic option for gastroesophageal reflux disease: A systematic review of clinical trials. Front Med (Lausanne) 2023; 10:997440. [PMID: 36873860 PMCID: PMC9981648 DOI: 10.3389/fmed.2023.997440] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
Background The main components of gastroesophageal reflux disease (GERD) management include a combination of medications and lifestyle modifications; Nevertheless, based on the severity of symptoms and their response to medications, other treatments could be considered. Baclofen has been demonstrated in studies to relieve GERD symptoms. The current study aimed to precisely address the effects of baclofen on the treatment of GERD and its characteristics. Methods A systematic search was carried out in Pubmed/Medline, Cochrane CENTRAL, Scopus, Google Scholar, Web of Science, and clinicaltrials.gov up to December 10, 2021. The search terms included baclofen, GABA agonists, GERD, and reflux. Results We selected 26 papers that matched the inclusion criteria after examining 727 records. Studies were classified into four categories based on the study population and reported outcomes: (1) adults, (2) children, (3) patients with gastroesophageal reflux-induced chronic cough, (4) hiatal hernia patients. The results revealed that baclofen can significantly improve reflux symptoms and pH-monitoring and manometry findings to different degrees in all four mentioned categories; although its effect on pH-monitoring parameters seems less significant than the other parameters. Mild neurological and mental status deterioration were the most reported side effects. However, side effects occurred in a portion of less than 5% of short-term users and nearly 20% of long-term users. Conclusion In PPI-resistant patients, a trial of adding baclofen to the PPI may be helpful. Baclofen therapies may be more beneficial for symptomatic GERD patients who also report concurrent conditions including alcohol use disorder, non-acid reflux, or obesity. Systematic review registration https://clinicaltrials.gov/.
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Affiliation(s)
- Erfan Arabpour
- Department of Gastroenterology and Hepatology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Khoshdel
- Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Akhgarzad
- Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadamin Abdi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Negin Tabatabaie
- Department of Internal Medicine, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Dorsa Alijanzadeh
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdehagh
- Department of Gastroenterology and Hepatology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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5
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Hung JS, Liang SW, Omari T, Wong MW, Lei WY, Yi CH, Liu TT, Lin L, Chen CL. Effects of the GABA(B) agonist baclofen on volitional swallowing in normal subjects. Kaohsiung J Med Sci 2023; 39:80-86. [PMID: 36245436 DOI: 10.1002/kjm2.12607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/01/2022] [Accepted: 09/13/2022] [Indexed: 01/15/2023] Open
Abstract
The GABA(B) receptor agonist baclofen is known to suppress the rate of spontaneous swallowing but not pharyngeal muscle contraction. The extent to which baclofen may alter volitional swallowing is not currently known. We investigated the effects of baclofen in healthy subjects, hypothesizing that baclofen exposure would alter volume-regulation and/or piecemeal deglutition behaviors during volitional swallowing attempts. Pharyngeal high-resolution manometry impedance (P-HRM-I) protocol was used to assess swallowing function of 22 healthy adult volunteers (median 29 years) who were investigated on two occasions, receiving 40 mg baclofen (oral) 1 h before study, or placebo (randomized). Standard swallow function variables recommended by the pharyngeal HRM Working Group were derived for 5 ml, 10 ml, and 20 ml volumes of thin and extremely thick liquid challenges. Multiple swallow behaviors, comprising two swallows <5 s apart, were characterized. The spontaneous swallow rate was also determined. Baclofen exposure had no overall significant effect on swallow variables. Upper esophageal sphincter pressure was weaker during exposure to baclofen, during both the pre-deglutitive and post-deglutitive phases of the swallow (p < 0.05 during thick liquid swallows). Piecemeal swallows, where the bolus is separated in two potions, were significantly more common during 20 ml boluses (p = 0.002). Baclofen decreased the frequency of piecemeal deglutition overall. Baclofen has limited to no effect on volitional swallowing measures, however, does reduce the likelihood of initiation of piecemeal deglutition to large volume challenges.
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Affiliation(s)
- Jui-Sheng Hung
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Shu-Wei Liang
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Taher Omari
- Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia
| | - Ming-Wun Wong
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Wei-Yi Lei
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Chih-Hsun Yi
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Tso-Tsai Liu
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Lin Lin
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
| | - Chien-Lin Chen
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan.,Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
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6
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Badri H, Gibbard C, Denton D, Satia I, Al-Sheklly B, Dockry RJ, Holt K, McGuiness K, Treadway S, Whorwell P, Houghton L, Lee A, Escott KJ, Lee T, Wilkinson G, Holt A, Canning BJ, Smith JA. A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin evoked coughs in patients with refractory chronic cough. ERJ Open Res 2022; 8:00546-2021. [PMID: 35295236 PMCID: PMC8918934 DOI: 10.1183/23120541.00546-2021] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 01/29/2022] [Indexed: 11/23/2022] Open
Abstract
Objective Baclofen is a centrally acting γ-aminobutyric acid type B (GABAB) receptor agonist which reduces gastro-oesophageal reflux and suppresses the cough reflex; however, central nervous system side-effects limit its use. Lesogaberan is a novel peripherally acting GABAB agonist, but its effects on refractory chronic cough are unknown. Design We performed a single-centre, placebo-controlled, double-blind randomised crossover study in patients with chronic cough, refractory to the treatment of underlying conditions. Patients were randomised to treatment with lesogaberan 120 mg modified release twice daily or matched placebo for 2 weeks and then crossed over to the alternative therapy after a 2-week washout. The primary end-point was 24-h cough frequency measured with an acoustic monitoring system. In addition, cough responses to capsaicin were measured, and gastro-oesophageal reflux assessed by 24-h pH/impedance at screening. Results 22 patients were randomised to receive lesogaberan/placebo or placebo/lesogaberan (female (73%); mean±sd age 63.7±7.2 years; median (interquartile range) cough duration 10.5 (5.8–17.0) years; mean (95% CI) 45 (29–67) reflux events in 24 h; two patients had abnormal oesophageal acid exposure times). Although lesogaberan reduced cough counts by 26% over placebo, this did not reach statistical significance (p=0.12). However, lesogaberan did significantly improve cough responses to capsaicin (p=0.04) and the number of cough bouts (p=0.04) compared with placebo. Lesogaberan was well tolerated in this study. Conclusions Lesogaberan improved cough hypersensitivity and the number of bouts of coughing, but not coughs per hour. This implies a possible role for peripheral GABAB receptors in refractory chronic cough. Lesogaberan, a peripherally acting GABAB agonist, does not reduce 24-h cough frequency in patients with chronic cough despite significantly reducing capsaicin-induced coughinghttps://bit.ly/3uGyPQL
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7
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Crespo MM, Claridge T, Domsic RT, Hartwig M, Kukreja J, Stratton K, Chan KM, Molina M, Ging P, Cochrane A, Hoetzenecker K, Ahmad U, Kapnadak S, Timofte I, Verleden G, Lyu D, Quddus S, Davis N, Porteous M, Mallea J, Perch M, Distler O, Highland K, Magnusson J, Vos R, Glanville AR. ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements. J Heart Lung Transplant 2021; 40:1279-1300. [PMID: 34474940 DOI: 10.1016/j.healun.2021.07.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/18/2022] Open
Abstract
Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there's no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients.
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Affiliation(s)
- Maria M Crespo
- Division of Pulmonary, Allergy and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Tamara Claridge
- Department of Pharmacy, Hospital of the University of University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robyn T Domsic
- Division of Rheumatology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Matthew Hartwig
- Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina
| | - Jasleen Kukreja
- Division of Thoracic Surgery, University of California San Francisco, San Francisco, California
| | - Kathleen Stratton
- Department of Pharmacy, Hospital of the University of University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kevin M Chan
- Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Maria Molina
- Department of Pharmacy, Hospital of the University of University of Pennsylvania, Philadelphia, Pennsylvania
| | - Patricia Ging
- Department of Pharmacy, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Adam Cochrane
- Department of Pharmacy, Inova Fairfax Hospital, Falls Church, Virginia
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Usman Ahmad
- Department of Cardiothoracic Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Siddhartha Kapnadak
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, Washington
| | - Irina Timofte
- Division of Pulmonary, University of Maryland Medical System, Baltimore, Maryland
| | - Geert Verleden
- Lung Transplant Unit, University Hospital of Gasthuisberg, Leuven, Belgium
| | - Dennis Lyu
- Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Sana Quddus
- Division of Pulmonary and Critical Care Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, Illinois
| | - Nicole Davis
- Lung Transplant Program, Tampa General Hospital, Tampa, Florida
| | - Mary Porteous
- Division of Pulmonary, Allergy and Critical Care Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jorge Mallea
- Division of Pulmonary, Allergy, and Critical Care, Mayo Clinic Florida, Jacksonville, Florida
| | - Michael Perch
- Lung Transplant Program, Rigshospitalet, Copenhagen, Denmark
| | - Olivier Distler
- Department of Rheumatology, University of Zurich Medical Center, Zurich, Switzerland
| | | | - Jesper Magnusson
- Department of Pulmonology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Robin Vos
- Lung Transplant Unit, University Hospital of Gasthuisberg, Leuven, Belgium
| | - Allan R Glanville
- The Lung Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia
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8
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Basnayake C, Geeraerts A, Pauwels A, Koek G, Vaezi M, Vanuytsel T, Tack J. Systematic review: duodenogastroesophageal (biliary) reflux prevalence, symptoms, oesophageal lesions and treatment. Aliment Pharmacol Ther 2021; 54:755-778. [PMID: 34313333 DOI: 10.1111/apt.16533] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/20/2021] [Accepted: 07/01/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The prevalence of duodenogastroesophageal reflux (DGER) and its effect on symptoms and oesophageal lesions in gastroesophageal reflux disease (GERD) is unclear. AIMS To conduct a systematic review to determine the prevalence of DGER among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. METHODS We searched Pubmed and MEDLINE for full text, English language articles until October 2020 that evaluated DGER prevalence among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. RESULTS We identified 3891 reports and included 35 which analysed DGER prevalence in GERD, 15 which evaluated its effect in non-erosive reflux disease (NERD), 17 on erosive oesophagitis, 23 in Barrett's, and 13 which evaluated the treatment of DGER. The prevalence of DGER, when evaluated by Bilitec, among all GERD patients ranged from 10% to 97%, in NERD 10%-63%, in erosive oesophagitis 22%-80% and in Barrett's 50%-100%. There were no differences in the presence or degree of DGER among patients who were asymptomatic or symptomatic on proton pump inhibitors (PPI). The most commonly evaluated treatments for DGER were PPIs and DGER reduced post-PPI therapy in all studies. CONCLUSIONS The prevalence of DGER increased with more advanced oesophageal lesions and did not explain persisting symptoms among patients taking PPI therapy. PPIs appear to be effective in the treatment of DGER. DGER remains an important consideration in patients with GERD and future therapies deserve more study.
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Affiliation(s)
- Chamara Basnayake
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium.,St Vincent's Hospital & University of Melbourne, Melbourne, VIC, Australia
| | - Annelies Geeraerts
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ans Pauwels
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ger Koek
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Michael Vaezi
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Jan Tack
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
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9
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Romito JW, Turner ER, Rosener JA, Coldiron L, Udipi A, Nohrn L, Tausiani J, Romito BT. Baclofen therapeutics, toxicity, and withdrawal: A narrative review. SAGE Open Med 2021; 9:20503121211022197. [PMID: 34158937 PMCID: PMC8182184 DOI: 10.1177/20503121211022197] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
Baclofen is an effective therapeutic for the treatment of spasticity related to multiple sclerosis, spinal cord injuries, and other spinal cord pathologies. It has been increasingly used off-label for the management of several disorders, including musculoskeletal pain, gastroesophageal reflux disease, and alcohol use disorder. Baclofen therapy is associated with potential complications, including life-threatening toxicity and withdrawal syndrome. These disorders require prompt recognition and a high index of suspicion. While these complications can develop following administration of either oral or intrathecal baclofen, the risk is greater with the intrathecal route. The management of baclofen toxicity is largely supportive while baclofen withdrawal syndrome is most effectively treated with re-initiation or supplementation of baclofen dosing. Administration of other pharmacologic adjuncts may be required to effectively treat associated withdrawal symptoms. This narrative review provides an overview of the historical and emerging uses of baclofen, offers practical dosing recommendations for both oral and intrathecal routes of administration, and reviews the diagnosis and management of both baclofen toxicity and withdrawal.
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Affiliation(s)
- Jia W Romito
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
- Department of Neurological Surgery, The
University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Neurology, The University
of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Emily R Turner
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - John A Rosener
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Landon Coldiron
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Ashutosh Udipi
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Linsey Nohrn
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Jacob Tausiani
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Bryan T Romito
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
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10
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Jeong SO, Lee JS, Lee TH, Hong SJ, Cho YK, Park J, Jeon SR, Kim HG, Kim JO. Characteristics of symptomatic belching in patients with belching disorder and patients who exhibit gastroesophageal reflux disease with belching. J Neurogastroenterol Motil 2021; 27:231-239. [PMID: 33424014 PMCID: PMC8026376 DOI: 10.5056/jnm20114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/02/2020] [Accepted: 08/16/2020] [Indexed: 12/19/2022] Open
Abstract
Background/Aims Belching disorder (BD) is clinically distinct from gastroesophageal reflux disease (GERD) with belching. Supragastric belching (SGB) is closely associated with reflux episodes. This study investigates belch characteristics in association with reflux, compared between patients with BD and those who had GERD with belching. Methods Impedance pH monitoring data from 10 patients with BD and 10 patients with GERD who exhibited belching were retrospectively analyzed. Belches were considered "isolated" or "reflux-related" and acidic/non-acidic. Belch characteristics were compared between patients with BD and those with GERD. Results Symptomatic belches were more frequent in patients with BD than in patients with GERD (median, 160.5 vs 56.0, P < 0.05). SGB was the most common type in both groups; common subtypes comprised "isolated" in patients with BD and "isolated during the reflux period" in patients with GERD. Reflux-related SGB was more common in patients with GERD than in BD (78.3% vs 45.2%, P < 0.005). Both "preceding belching" including the reflux period and acidic SGB were more common in patients with GERD than in BD (31.8% vs 8.6% and 38.1% vs 8.9%, both P < 0.05). Supragastric belch number positively correlated with all reflux episodes in patients with GERD (adjusted R2 = 0.572, P = 0.007). Conclusions BD is characterized by more belching, compared to GERD. SGB is more frequently associated with reflux in GERD than in BD; acidity may be related to GERD. In BD, SGB is typically non-acidic and unrelated to reflux. Distinct SGB characteristics may reflect different pathogenic mechanisms of reflux and associated symptoms.
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Affiliation(s)
- Shin Ok Jeong
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
| | - Joon Seong Lee
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
| | - Tae Hee Lee
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
| | - Su Jin Hong
- Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Gyeonggi-do, Korea
| | - Young Kyu Cho
- Division of Gastroenterology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Chungcheongnam-do, Korea
| | - Junseok Park
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seong Ran Jeon
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
| | - Hyun Gun Kim
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jin-Oh Kim
- Institute for Digestive Research, Digestive Disease Center Soonchunhyang University College of Medicine, Seoul, Korea
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11
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Chahuan J, Rey P, Monrroy H. Rumination syndrome. A review article. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021. [DOI: 10.1016/j.rgmxen.2020.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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12
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Chahuan J, Rey P, Monrroy H. Rumination syndrome. A review article. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021; 86:163-171. [PMID: 33602544 DOI: 10.1016/j.rgmx.2020.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 11/11/2020] [Accepted: 11/13/2020] [Indexed: 02/07/2023]
Abstract
Rumination syndrome is a functional gastrointestinal disorder characterized by effortless postprandial regurgitation of ingested food into the mouth. An unperceived postprandial contraction of the abdominal wall could be a key mechanism. In those patients, retrograde flow of the ingested gastric content into the mouth is produced due to a simultaneous combination of elevated intra-abdominal pressure and negative intrathoracic pressure. The estimated prevalence is around 2% in the general adult population. The main clinical characteristics include: a) early postprandial regurgitation, b) the effortlessly regurgitated material is similar to the ingested food, c) the regurgitated material is spit out or swallowed again. The clinical diagnosis of rumination syndrome relies on the clinical criteria. High resolution esophageal manometry, ideally including impedance monitoring, can be an important adjunct for making the clinical diagnosis. Its management is based on instruction as to the nature of the pathology, education in postprandial diaphragmatic breathing, and the assessment of possible psychiatric comorbidity. Baclofen use is reserved for second-line treatment in patients with refractory symptoms.
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Affiliation(s)
- J Chahuan
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - P Rey
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Laboratorio de Fisiología Digestiva, Red de Salud UC-Christus, Santiago, Chile
| | - H Monrroy
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Laboratorio de Fisiología Digestiva, Red de Salud UC-Christus, Santiago, Chile.
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13
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Bhagat K, Singh JV, Pagare PP, Kumar N, Sharma A, Kaur G, Kinarivala N, Gandu S, Singh H, Sharma S, Bedi PMS. Rational approaches for the design of various GABA modulators and their clinical progression. Mol Divers 2021; 25:551-601. [PMID: 32170466 PMCID: PMC8422677 DOI: 10.1007/s11030-020-10068-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 02/28/2020] [Indexed: 12/20/2022]
Abstract
GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.
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Affiliation(s)
- Kavita Bhagat
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India
| | - Jatinder V Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India
| | - Piyusha P Pagare
- Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, 23219, USA
| | - Nitish Kumar
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India
| | - Anchal Sharma
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India
| | - Gurinder Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India
| | - Nihar Kinarivala
- Program in Chemical Biology, Sloan Kettering Institute, New York, NY, 10065, USA
| | - Srinivasa Gandu
- Department of Cell Biology and Neuroscience, Cell and Development Biology Graduate Program, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Harbinder Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India.
| | - Sahil Sharma
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India.
- Program in Chemical Biology, Sloan Kettering Institute, New York, NY, 10065, USA.
| | - Preet Mohinder S Bedi
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, PB, 143005, India.
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14
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Rybak A, Sethuraman A, Nikaki K, Koeglmeier J, Lindley K, Borrelli O. Gastroesophageal Reflux Disease and Foregut Dysmotility in Children with Intestinal Failure. Nutrients 2020; 12:nu12113536. [PMID: 33217928 PMCID: PMC7698758 DOI: 10.3390/nu12113536] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/09/2020] [Accepted: 11/12/2020] [Indexed: 12/16/2022] Open
Abstract
Gastrointestinal dysmotility is a common problem in a subgroup of children with intestinal failure (IF), including short bowel syndrome (SBS) and pediatric intestinal pseudo-obstruction (PIPO). It contributes significantly to the increased morbidity and decreased quality of life in this patient population. Impaired gastrointestinal (GI) motility in IF arises from either loss of GI function due to the primary disorder (e.g., neuropathic or myopathic disorder in the PIPO syndrome) and/or a critical reduction in gut mass. Abnormalities of the anatomy, enteric hormone secretion and neural supply in IF can result in rapid transit, ineffective antegrade peristalsis, delayed gastric emptying or gastroesophageal reflux. Understanding the underlying pathophysiologic mechanism(s) of the enteric dysmotility in IF helps us to plan an appropriate diagnostic workup and apply individually tailored nutritional and pharmacological management, which might ultimately lead to an overall improvement in the quality of life and increase in enteral tolerance. In this review, we have focused on the pathogenesis of GI dysmotility in children with IF, as well as the management and treatment options.
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Affiliation(s)
- Anna Rybak
- Department of Gastroenterology, the Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK; (A.S.); (J.K.); (K.L.); (O.B.)
- Correspondence:
| | - Aruna Sethuraman
- Department of Gastroenterology, the Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK; (A.S.); (J.K.); (K.L.); (O.B.)
| | - Kornilia Nikaki
- Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, 26 Ashfield Street, Whitechapel, London E1 2AJ, UK;
| | - Jutta Koeglmeier
- Department of Gastroenterology, the Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK; (A.S.); (J.K.); (K.L.); (O.B.)
| | - Keith Lindley
- Department of Gastroenterology, the Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK; (A.S.); (J.K.); (K.L.); (O.B.)
| | - Osvaldo Borrelli
- Department of Gastroenterology, the Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK; (A.S.); (J.K.); (K.L.); (O.B.)
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15
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Ribolsi M, de Carlo G, Balestrieri P, Guarino MPL, Cicala M. Understanding the relationship between esophageal motor disorders and reflux disease. Expert Rev Gastroenterol Hepatol 2020; 14:933-940. [PMID: 32658587 DOI: 10.1080/17474124.2020.1791703] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 07/01/2020] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The management of gastro-esophageal reflux disease (GERD) patients is often complex as the clinical presentation is heterogeneous and the mechanisms underlying symptoms are multifactorial. In the past decades, investigations conducted with conventional manometry and, above all, the more accurate high resolution manometry (HRM), helped us in exploring the field of esophageal motility and in understanding the link between motor features and GERD pathogenesis. AREAS COVERED Several studies carried out with conventional manometry and HRM have confirmed a relevant role of esophageal motor function in GERD pathogenesis. In particular, HRM studies have shown a direct correlation between impaired esophageal body motility, disruption of the esophagogastric junction and reflux burden. These findings impact the clinical and therapeutical management of GERD patients. Moreover, HRM findings might be helpful in evaluating patients with proton pump inhibitor (PPI) resistance and inconclusive evidences of GERD. EXPERT OPINION The relationship between esophageal motility and GERD pathogenesis needs to be further evaluated by multicenter outcome studies involving a large number of GERD patients and healthy controls. However, other more promising areas could be progressed.
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Affiliation(s)
- Mentore Ribolsi
- Unit of Gastroenterology and Digestive Endoscopy, Campus Bio Medico University , Rome, Italy
| | - Giovanni de Carlo
- Unit of Gastroenterology and Digestive Endoscopy, Campus Bio Medico University , Rome, Italy
| | - Paola Balestrieri
- Unit of Gastroenterology and Digestive Endoscopy, Campus Bio Medico University , Rome, Italy
| | | | - Michele Cicala
- Unit of Gastroenterology and Digestive Endoscopy, Campus Bio Medico University , Rome, Italy
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16
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Zhang M, Zhu Y, Dong R, Qiu Z. Gabapentin versus baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough. J Thorac Dis 2020; 12:5243-5250. [PMID: 33145100 PMCID: PMC7578446 DOI: 10.21037/jtd-2020-icc-002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Refractory gastroesophageal reflux-induced chronic cough (GERC) is a special type of gastroesophageal reflux disease (GERD) with predominant cough resistant to pragmatic standard anti-reflux therapy including antisecretory agents alone or in combination with promotility agents but with a favorable response to intensified anti-reflux treatment. The condition is not rare and is difficult to treat. Neuromodulators such as baclofen and gabapentin are considered potential therapeutic options for refractory GERC. Limited data indicate that gabapentin and baclofen could attenuate the cough symptom in patients with refractory GERC by blockade of gastroesophageal reflux or by direct antitussive effects. However, no study has compared the efficacy of these two drugs in treatment of refractory GERC. In an open-labeled randomized clinical study, we demonstrated that, as add-on therapy, gabapentin and baclofen had a similar prevalence of therapeutic success for suspected refractory GERC but gabapentin may be more preferable because of its fewer central side effects. The efficacy of baclofen and gabapentin was suboptimal, so further studies are needed to select the patients with refractory GERC suitable for precise treatment using these two neuromodulators.
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Affiliation(s)
- Mengru Zhang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yiqing Zhu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ran Dong
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongmin Qiu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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17
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Scarpignato C, Sloan JA, Wang DH, Hunt RH. Gastrointestinal pharmacology: practical tips for the esophagologist. Ann N Y Acad Sci 2020; 1481:90-107. [PMID: 32822080 DOI: 10.1111/nyas.14447] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/19/2020] [Accepted: 07/05/2020] [Indexed: 12/22/2022]
Abstract
Gastroesophageal reflux disease (GERD) is primarily a motor disorder, and its pathogenesis is multifactorial. As a consequence, treatment should be able to address the underlying pathophysiology. Proton pump inhibitors (PPIs) are the mainstay of medical therapy for GERD, but these drugs only provide the control of symptoms and lesions without curing the disease. However, continuous acid suppression with PPIs is recommended for patients with Barrett's esophagus because of their potential chemopreventive effects. In addition to the antisecretory activity, these compounds display several pharmacological properties, often overlooked in clinical practice. PPIs can indeed affect gastric motility, exert a mucosal protective effect, and an antioxidant, anti-inflammatory, and antineoplastic activity, also protecting cancer cells from developing chemo- or radiotherapeutic resistance. Even in the third millennium, current pharmacologic approaches to address GERD are limited. Reflux inhibitors represent a promise unfulfilled, effective and safe prokinetics are lacking, and antidepressants, despite being effective in selected patients, give rise to adverse events in a large proportion of them. While waiting for new drug classes (like potassium-competitive acid blockers), reassessing old drugs (namely alginate-containing formulations), and paving the new avenue of esophageal mucosal protection are, at the present time, the only reliable alternatives to acid suppression.
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Affiliation(s)
- Carmelo Scarpignato
- Department of Health Sciences, United Campus of Malta, Msida, Malta.,Faculty of Medicine, Chinese University of Hong Kong, ShaTin, Hong Kong
| | - Joshua A Sloan
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - David H Wang
- Division of Hematology and Oncology, UT Southwestern Medical Center and VA North Texas Health Care System, Dallas, Texas
| | - Richard H Hunt
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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18
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Zad M, Bredenoord AJ. Chronic Burping and Belching. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2020; 18:33-42. [PMID: 31974815 DOI: 10.1007/s11938-020-00276-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Belching is a physiological event that allows venting of swallowed gastric air. Excessive belching is a common presentation to gastroenterology clinics and could be isolated complains or associated with other gastrointestinal problems. PURPOSE OF THIS REVIEW: It is to describe the presentation, diagnosis, and treatment of belching disorders RECENT FINDINGS: These demonstrate that learned abnormal behaviors in response to unpleasant feeling in the abdomen are the driving causes for excessive belching and addressing these behaviors by speech pathology and cognitive behavior therapy considered as the keystone in its management SUMMARY: The gold standard in the diagnosis of belching is impedance monitoring by which belching is classified into supragastric belching and gastric belching.
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Affiliation(s)
- M Zad
- Department of gastroenterology, Hervey Bay Hospital, Queensland, Australia
| | - A J Bredenoord
- Department of Gastroenterology & Hepatology, Amsterdam UMC, location AMC, Academic Medical Centre, Amsterdam, PO Box 22660, 1100, DD, Amsterdam, the Netherlands.
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19
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Hung JS, Yi CH, Liu TT, Lei WY, Wong MW, Chen CL. Effects of GABA-B agonist baclofen on esophageal motility: Studies using high-resolution manometry. Neurogastroenterol Motil 2019; 31:e13716. [PMID: 31565828 DOI: 10.1111/nmo.13716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/19/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIM Baclofen inhibits transient lower esophageal sphincter (LES) relaxation. This study aimed to investigate the effect of baclofen on esophageal peristaltic function and contraction reserve in healthy adults using high-resolution manometry (HRM). METHODS Fifteen subjects underwent HRM with ten water swallows and five multiple rapid swallows (MRS) 90 minutes after oral intake of either baclofen or placebo on separate days at least 1 week apart. HRM parameters assessed included esophagogastric junction contractile integral (EGJ-CI), resting LES pressure, 4-second integrated relaxation pressure (IRP-4s), distal contractile integral (DCI), distal latency, peristaltic breaks, resting upper esophageal sphincter (UES) pressure, and contractile response to MRS. RESULTS Baclofen significantly increased EGJ-CI (P = .007), IRP-4s (P = .003), and LES pressure (P = .004). UES pressure, latency, and DCI were similar between baclofen and placebo (P = .87, P = .84, and P = .54, respectively). There was no difference in contractile response and peristaltic augmentation following MRS between baclofen and placebo (93% vs 100%, P = .30; 53% vs. 73%, P = .26, respectively). CONCLUSIONS Baclofen increases resting LES pressure and EGJ barrier function, but has no effect on primary peristalsis or contraction reserve.
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Affiliation(s)
- Jui-Sheng Hung
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Chih-Hsun Yi
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Tso-Tsai Liu
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Wei-Yi Lei
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Ming-Wun Wong
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
| | - Chien-Lin Chen
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
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20
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Wong MW, Hung JS, Liu TT, Yi CH, Lei WY, Chen CL. Gamma-aminobutyric acid receptor type B agonist baclofen inhibits acid-induced excitation of secondary peristalsis but not heartburn sensation. J Gastroenterol Hepatol 2019; 34:370-375. [PMID: 30069912 DOI: 10.1111/jgh.14404] [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: 05/02/2018] [Revised: 07/02/2018] [Accepted: 07/25/2018] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Acute esophageal acid infusion promotes distension-induced secondary peristalsis. The gamma-aminobutyric acid receptor type B (GABA-B) receptors activation inhibits secondary peristalsis. This study aimed to test the hypothesis whether acid excitation of secondary peristalsis can be influenced by baclofen. METHODS Secondary peristalsis was performed with intra-esophageal slow and rapid air injections in 13 healthy subjects. Direct esophageal infusion of 0.1 N HCl following pretreatment with placebo or baclofen was randomly performed at least 1 week apart. Symptom intensity, distension thresholds, and peristaltic parameters were determined and compared between each study protocol. RESULTS The intensity of heartburn symptom in response to esophageal acid infusion was significantly greater with baclofen than the placebo (P = 0.002). The threshold volume of secondary peristalsis during slow air injections in response to acid infusion was significantly greater with baclofen than the placebo (P = 0.001). Baclofen significantly increased the threshold volume of secondary peristalsis during rapid air injections in response to acid infusion (P = 0.001). The frequency of secondary peristalsis in response to acid infusion was significantly decreased by baclofen as compared with the placebo (P = 0.001). Baclofen significantly decreased peristaltic amplitudes in response to acid infusion during rapid air injections (P = 0.007). CONCLUSIONS Gamma-aminobutyric acid receptor type B agonist baclofen inhibits acid excitation of secondary peristalsis in human esophagus, which is probably mediated by both muscular and mucosal mechanoreceptors. This work supports the evidence of potential involvement of GABA-B receptors in negative modulation of acid excitation of esophageal perception as well as secondary peristalsis.
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Affiliation(s)
- Ming-Wun Wong
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University.,PhD Program in Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan
| | - Jui-Sheng Hung
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University
| | - Tso-Tsai Liu
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University
| | - Chih-Hsun Yi
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University
| | - Wei-Yi Lei
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University
| | - Chien-Lin Chen
- Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University
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21
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Rangan V, George NS, Khan F, Geng Z, Gabbard S, Kichler A, Gittleman H, Fass R. Severity of ineffective esophageal motility is associated with utilization of skeletal muscle relaxant medications. Neurogastroenterol Motil 2018; 30:e13235. [PMID: 29027725 DOI: 10.1111/nmo.13235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/19/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND Ineffective esophageal motility (IEM) is the most common finding on high-resolution esophageal manometry (HREM). The underlying mechanisms for IEM remain to be fully elucidated. The aim of this study was to determine if utilization of skeletal muscle relaxants is associated with IEM, and with more severe subtypes of the disorder. METHODS Patients with diagnosis of IEM were gender and age matched to patients with normal HREM. Demographic information, symptoms, endoscopic findings, medication usage and medical comorbidities were recorded. Patients with a diagnosis of IEM were divided into subgroups based on mean distal contractile integral (DCI) and percentage of ineffective swallows, and assessed for clinically significant differences among patients with varying severity of underlying IEM. KEY RESULTS A total of 118 patients were included in each group. There were no significant clinical differences between the group of patients with IEM and the group of patients with normal manometry. Within the group of IEM patients, those with mean DCI < 250 mm Hg/s/cm were more likely to be prescribed skeletal muscle relaxants (27.8% vs 11.0%, P = .044), and those using skeletal muscle relaxants had a larger mean percentage of ineffective swallows (81.1% vs 71.5%, P = .029). There were no significant differences across mean DCI subgroups in usage of any other medication, or in any of the demographic variables or disease comorbidities examined in this study. CONCLUSIONS & INFERENCES Use of skeletal muscle relaxants is associated with more severe IEM, which may suggest a causal association between this class of medications and weaker esophageal peristalsis.
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Affiliation(s)
- V Rangan
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Cleveland, OH, USA.,Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - N S George
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Cleveland, OH, USA.,Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - F Khan
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Cleveland, OH, USA.,Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Z Geng
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Cleveland, OH, USA.,Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - S Gabbard
- The Esophageal Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
| | - A Kichler
- The Esophageal Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
| | - H Gittleman
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - R Fass
- The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Cleveland, OH, USA.,Case Western Reserve University School of Medicine, Cleveland, OH, USA
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22
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Clarke JO, Fernandez-Becker NQ, Regalia KA, Triadafilopoulos G. Baclofen and gastroesophageal reflux disease: seeing the forest through the trees. Clin Transl Gastroenterol 2018; 9:137. [PMID: 29599487 PMCID: PMC5876385 DOI: 10.1038/s41424-018-0010-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 02/06/2018] [Indexed: 12/19/2022] Open
Abstract
Baclofen has been shown to decrease reflux events and increase lower esophageal sphincter pressure, yet has never established a clear role in the treatment of gastroesophageal reflux disease (GERD). Lei and colleagues have shown in a recent elegant study that baclofen reduces the frequency and initiation of secondary peristalsis and heightens esophageal sensitivity to capsaicin-mediated stimulation. These findings may help explain both the benefit of baclofen in conditions such as rumination and supragastric belching, as well as the apparent lack of benefit of baclofen and other GABAB agonists in long-term treatment of GERD.
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Affiliation(s)
- John O Clarke
- Stanford Multidimensional Program for Innovation and Research in the Esophagus (S-MPIRE) Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
| | - Nielsen Q Fernandez-Becker
- Stanford Multidimensional Program for Innovation and Research in the Esophagus (S-MPIRE) Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Kirsten A Regalia
- Stanford Multidimensional Program for Innovation and Research in the Esophagus (S-MPIRE) Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - George Triadafilopoulos
- Stanford Multidimensional Program for Innovation and Research in the Esophagus (S-MPIRE) Division of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, CA, 94305, USA
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23
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Kung YM, Hsu WH, Wu MC, Wang JW, Liu CJ, Su YC, Kuo CH, Kuo FC, Wu DC, Wang YK. Recent Advances in the Pharmacological Management of Gastroesophageal Reflux Disease. Dig Dis Sci 2017; 62:3298-3316. [PMID: 29110162 DOI: 10.1007/s10620-017-4830-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/25/2017] [Indexed: 12/15/2022]
Abstract
The management of proton pump inhibitor-refractory GERD (rGERD) is a challenge in clinical practice. Since up to one-third of patients with typical GERD symptoms (heartburn and/or acid regurgitation) are not satisfied with proton pump inhibitor (PPI) therapy, new drug development targeting different pathophysiologies of GERD is imperative. At present, no other drugs serve as a more potent acid suppression agent than PPIs. As an add-on therapy, histamine type-2 receptor antagonists, alginates, prokinetics and transient lower esophageal sphincter relaxation inhibitors have some impact on the subgroups of rGERD, but greater effectiveness and fewer adverse effects for widespread use are required. Visceral hypersensitivity also contributes to the perception of GERD symptoms, and neuromodulators including antidepressants play a role in this category. Esophageal pH-impedance monitoring helps to distinguish functional heartburn from true GERD, and psychologic medication and cognitive behavior therapy are further therapy options instead of PPIs.
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Affiliation(s)
- Yu-Min Kung
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, 100 Tz-You 1st road, Kaohsiung, 807, Taiwan
| | - Wen-Hung Hsu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Medicine, Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Meng-Chieh Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Jiunn-Wei Wang
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Chung-Jung Liu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yu-Chung Su
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Medicine, Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Hung Kuo
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Medicine, Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Fu-Chen Kuo
- School of Medicine, College of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Faculty of Medicine, Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Yao-Kuang Wang
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. .,Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, 100 Tz-You 1st road, Kaohsiung, 807, Taiwan.
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24
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Iwakiri K. Treatment Strategy for Standard-Dose Proton Pump Inhibitor-Resistant Reflux Esophagitis. J NIPPON MED SCH 2017; 84:209-214. [PMID: 29142181 DOI: 10.1272/jnms.84.209] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Reflux esophagitis is characterized by excessive esophageal acid exposure. To treat reflux esophagitis, it is necessary to reduce excessive esophageal acid exposure to within the normal range. The first-line drug for the treatment of reflux esophagitis is a standard-dose proton-pump inhibitor (PPI), which is also recommended by the Evidence-based Clinical Practice Guidelines 2015 for gastroesophageal disease of the Japanese Society of Gastroenterology. It has been reported that the response to a standard dose of PPI in patients with mild reflux esophagitis is 90-100%, and that in patients with severe reflux esophagitis is 80-85%. However, PPI-resistant reflux esophagitis has been increasing. When the standard dose of PPI is not effective, modification of the lifestyle with PPI therapy, switching to another PPI, or a change in the administration method (before meals), as well as double-dose PPI (in divided doses), may be effective. In addition, vonoprazan (potassium-competitive acid blocker), which has rapid and potent acid-suppressive effects, became available in February 2015 in Japan. In the clinical trial data, vonoprazan is very effective for reflux esophagitis. However, clinical data on vonoprazan are still insufficient. The establishment of a new treatment for reflux esophagitis taking advantage of the rapid and potent acid-suppressive effects is awaited.
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Affiliation(s)
- Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine
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25
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Influence of GABA-B Agonist Baclofen on Capsaicin-Induced Excitation of Secondary Peristalsis in Humans. Clin Transl Gastroenterol 2017; 8:e120. [PMID: 28981081 PMCID: PMC5666117 DOI: 10.1038/ctg.2017.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 08/15/2017] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES Esophageal instillation of capsaicin enhances secondary peristalsis, but the γ-aminobutyric acid receptor type B (GABA-B) agonist baclofen inhibits secondary peristalsis. This study aimed to investigate whether baclofen could influence heartburn perception and secondary peristalsis subsequent to capsaicin infusion in healthy adults. METHODS Secondary peristalsis was performed by slow and rapid mid-esophagus air injections in 15 healthy subjects. Two different sessions including esophageal infusion of capsaicin-containing red pepper sauce (0.84 mg) following pre-treatment with placebo or baclofen were randomly performed to test the effects on heartburn perception and secondary peristalsis. RESULTS The intensity of heartburn symptom subsequent to capsaicin infusion was significantly greater after pre-treatment of baclofen as compared with the placebo (P=0.03). Baclofen significantly increased the threshold volume of secondary peristalsis to slow air injections subsequent to esophageal capsaicin infusion (P<0.001). Baclofen significantly increased the threshold volume of secondary peristalsis to rapid air injections subsequent to esophageal capsaicin infusion (P<0.01). The frequency of secondary peristalsis subsequent to capsaicin infusion was significantly decreased with baclofen as compared with the placebo (P<0.002). Baclofen had no effect on any of the peristaltic parameters of secondary peristalsis subsequent to capsaicin infusion. CONCLUSIONS The GABA-B agonist baclofen appears to attenuate the esophagus to capsaicin-induced excitation of secondary peristalsis in healthy adults. Our study suggests the inhibitory modulation for GABA-B receptors on capsaicin-sensitive afferents mediating secondary peristalsis in human esophagus.
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26
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Rouzade-Dominguez ML, Pezous N, David OJ, Tutuian R, Bruley des Varannes S, Tack J, Malfertheiner P, Allescher HD, Ufer M, Rühl A. The selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056) reduces the incidence of reflux episodes in dogs and patients with moderate to severe gastroesophageal reflux disease. Neurogastroenterol Motil 2017; 29. [PMID: 28337838 DOI: 10.1111/nmo.13058] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 02/07/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Transient lower esophageal sphincter relaxations (TLESRs) induced by gastric distension are modulated by the metabotropic glutamate receptor 5 (mGluR5) that influences the vagal reflex loop. We therefore aimed to examine the effects of the selective mGluR5 antagonist mavoglurant (AFQ056) on the number of TLESRs in dogs and reflux episodes in patients with gastroesophageal reflux disease (GERD). METHODS In a dog model, the number of meal-induced TLESRs was determined after intravenous (0.03, 0.1, 0.3, and 1 mg kg-1 ) and oral (1, 3, and 10 mg kg-1 ) doses of mavoglurant with reference to vehicle. In a multicenter, randomized, double-blind, placebo-controlled, three-period crossover study, the incidence of meal-induced reflux episodes was assessed by esophageal impedance monitoring after single, oral doses of mavoglurant (50 and 400 mg) or baclofen (40 mg) in 30 patients with moderate to severe GERD. KEY RESULTS In dogs, mavoglurant reduced the number of TLESRs after intravenous and oral administration. In patients with GERD, the incidence of postprandial reflux episodes was significantly lower at a dose of 400 mg mavoglurant (-37.5% ; 90% confidence interval [CI]: -57.8, -17.2), whereas there was no significant difference at 50 mg of mavoglurant compared to placebo. A significantly lower incidence of reflux episodes was also noted with the active comparator baclofen (-50.3%; 90% CI: -66.2, -34.3), thereby validating this study. CONCLUSIONS AND INFERENCES These data suggest a potential clinical benefit of mGluR5 antagonists such as mavoglurant in patients with GERD, particularly in those with persisting symptoms despite treatment with proton pump inhibitors.
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Affiliation(s)
| | - N Pezous
- Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
| | - O J David
- Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
| | - R Tutuian
- Universitätsspital Zürich, Zürich, Switzerland
| | | | - J Tack
- University Hospitals Leuven, Leuven, Belgium
| | | | - H-D Allescher
- Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany
| | - M Ufer
- Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
| | - A Rühl
- Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland
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27
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Scarpellini E, Pauwels A, Vos R, Rommel N, Tack J. Effect of methylnaltrexone and naloxone on esophageal motor function in man. Neurogastroenterol Motil 2017; 29. [PMID: 28110513 DOI: 10.1111/nmo.12938] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 08/08/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Endogenous opioids (EO) acting on μ-opiod receptors in central and enteric nervous system (ENS) control gastrointestinal motility but it is still unclear whether EO in ENS may control esophageal function in man, thus we will study the effects of methylnaltrexone (MNTX), a peripherally selective, and naloxone (NA), a non-selective μ-opiod receptor antagonist, on esophageal motility in healthy subjects. METHODS Fifteen HV (6 M; 34.1 ± 0.6 years; BMI: 22.1 ± 0.1 kg/m2 ) underwent three esophageal high-resolution manometry impedance (HRiM) studies with 10 saline swallows administered every 30 minutes: drug was administered after 30 minutes (MNTX subcutaneously/NA or saline intravenously), a solid meal after 90 minutes; measurements continued for 120 minutes postprandially. KEY RESULTS Methylnaltrexone did not significantly decrease the upper esophageal sphincter (UES) percentage of relaxation preprandially (72.5 ± 5 vs 66.9 ± 4.6 and 73 ± 3.8%, ANOVA between placebo, MNTX and NA, P=NS) and postprandially (60 minutes: 68.2 ± 5.6 vs 61 ± 5.5 and 67.1 ± 5.6%; 120 minutes: 68 ± 5.9 vs 59.3 ± 5.2 and 67.7 ± 4.7%; ANOVA between placebo, MNTX and NA, P=NS). MNTX and NA did not significantly alter preprandial and postprandial LES resting pressures and integrated relaxation pressure (ANOVA between placebo, MNTX and NA, all P=NS). Peak front velocity and distal contractile integral were not altered pre- and postprandially by MNTX and NA (ANOVA between placebo, MNTX and NA, P=NS). Transient lower esophageal sphincter relaxations (TLESRs') number was not altered by MNTX and NA (ANOVA between placebo, MNTX and NA, all P=NS). CONCLUSIONS AND INFERENCES The peripheral selective and non-selective μ-opioid receptor antagonists MNTX and NA, respectively, do not alter TLESRs occurrence and esophageal peristalsis.
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Affiliation(s)
- E Scarpellini
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - A Pauwels
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - R Vos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - N Rommel
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - J Tack
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
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28
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Lo WK, Mashimo H. Medical Management of GERD: Algorithms and Outcomes. FAILED ANTI-REFLUX THERAPY 2017:19-23. [DOI: 10.1007/978-3-319-46885-3_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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29
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Scarpellini E, Boecxstaens V, Broers C, Vos R, Pauwels A, Tack J. Effect of baclofen on gastric acid pocket in subjects with gastroesophageal reflux disease symptoms. Dis Esophagus 2016; 29:1054-1063. [PMID: 26541138 DOI: 10.1111/dote.12443] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Postprandial gastroesophageal reflux (PGER) in the distal esophagus (DE) is associated with a gastric juice 'acid pocket' (AP). Baclofen reduces AP extension into the DE in healthy volunteers, in part through increased lower esophageal sphincter (LES) pressure. We aimed to verify whether baclofen also affects postprandial AP location and extent in gastroesophageal reflux disease (GERD) patients. Thirteen treatment-naive heartburn-prevalent GERD patients underwent two AP studies, after pretreatment with baclofen 40 mg or placebo 30 minutes preprandially. We performed pH-probe stepwise pull-throughs (PT) (1 cm/min, LES -10 to +5 cm) before and every 30 minutes from 30 minutes before up to 150 minutes after a test meal. After the meal, both after placebo and baclofen, gastric pH significantly dropped at 30, 60, 90 minutes postprandially (P: nadir pHs of 3.9 ± 0.6, 2.3 ± 0.6, 2.1 ± 0.4; B: nadir pHs of 2.5 ± 0.4, 2.8 ± 0.4, 2.5 ± 0.3; all P < 0.05). After placebo, LES pressure decreased at 60, 90 and 120 minutes postprandially (32.7 ± 6.1 vs. 24.5 ± 3.1, 27.3 ± 5.9, 27.3 ± 6.0 mmHg; analysis of variance [ANOVA], P = 0.037), but this was prevented by baclofen (25.4 ± 3.4 vs. 29.4 ± 2, 32.2 ± 1.4, 35.5 ± 1.7 mmHg, ANOVA, P = not significant (NS)). Baclofen did not significantly decrease the postprandial AP extent above the LES but prevented the postprandial increase in transient lower esophageal sphincter relaxations (TLESRs) (preprandial vs. postprandial, placebo: 1.1 ± 0.3 vs. 3.7 ± 0.7, P < 0.05; baclofen: 1.4 ± 0.4 vs. 2 ± 0.5, P = NS). In GERD patients, baclofen significantly increases postprandial LES pressure, prevents the increase TLESRs but, unlike in healthy volunteers, does not affect AP extension into the DE.
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Affiliation(s)
- E Scarpellini
- TARGID (Translational Research Centre for Gastrointestinal Disorders), University of Leuven, Leuven, Belgium
| | - V Boecxstaens
- TARGID (Translational Research Centre for Gastrointestinal Disorders), University of Leuven, Leuven, Belgium
| | - C Broers
- TARGID (Translational Research Centre for Gastrointestinal Disorders), University of Leuven, Leuven, Belgium
| | - R Vos
- TARGID (Translational Research Centre for Gastrointestinal Disorders), University of Leuven, Leuven, Belgium
| | - A Pauwels
- TARGID (Translational Research Centre for Gastrointestinal Disorders), University of Leuven, Leuven, Belgium
| | - J Tack
- TARGID (Translational Research Centre for Gastrointestinal Disorders), University of Leuven, Leuven, Belgium
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30
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Abdel Jalil AA, Castell DO. Ineffective Esophageal Motility (IEM): the Old-New Frontier in Esophagology. Curr Gastroenterol Rep 2016; 18:1. [PMID: 26685862 DOI: 10.1007/s11894-015-0472-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Ineffective esophageal motility (IEM) is characterized by distal esophageal contraction amplitude of <30 mmHg on conventional manometry (Blonski et al. Am J Gastroenterol. 103(3):699-704, 2008), or a distal contractile integral (DCI) < 450 mmHg*s*cm on high-resolution manometry (HRM) (Kahrilas et al. Neurogastroenterol Motil. 27(2):160-74, 2015) in≥50 % of test swallows. IEM is the most common abnormality on esophageal manometry, with an estimated prevalence of 20-30 % (Tutuian and Castell Am J Gastroenterol. 99(6):1011-9, 2004; Conchillo et al. Am J Gastroenterol. 100(12):2624-32, 2005). Non-obstructive dysphagia has been considered to be frequently associated with severe esophageal peristaltic dysfunction. Defective bolus transit (DBT) on multichannel intraluminal impedance testing was found in more than half of IEM patients who presented with dysphagia (Tutuian and Castell Am J Gastroenterol. 99(6):1011-9, 2004), highlighting the functional defect of this manometric finding. Treatment of IEM has been challenging because of lack of promotility agents that have a definite effect on esophageal function.
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Affiliation(s)
- Ala' A Abdel Jalil
- Division of Gastroenterology & Hepatology, University of Missouri-Columbia, One Hospital Dr., CE 405, Columbia, MO, 65212, USA.
| | - Donald O Castell
- Esophageal Disorders Program, Gastroenterology & Hepatology Division, Medical University of South Carolina (MUSC), 114 Doughty St. Suite 249, MSC 702, Charleston, SC, 29425, USA.
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31
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de Bortoli N, Ottonello A, Zerbib F, Sifrim D, Gyawali CP, Savarino E. Between GERD and NERD: the relevance of weakly acidic reflux. Ann N Y Acad Sci 2016; 1380:218-229. [DOI: 10.1111/nyas.13169] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 06/04/2016] [Accepted: 06/13/2016] [Indexed: 12/14/2022]
Affiliation(s)
- Nicola de Bortoli
- Division of Gastroenterology, Department of Translational Research and New Technology in Medicine and Surgery; University of Pisa; Pisa Italy
| | - Andrea Ottonello
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology; University of Padua; Padua Italy
| | - Frank Zerbib
- Department of Gastroenterology; CHU Bordeaux and Bordeaux University; Bordeaux France
| | - Daniel Sifrim
- Barts and the London School of Medicine and Dentistry; Queen Mary University of London; United Kingdom
| | - C. Prakash Gyawali
- Division of Gastroenterology; Washington University School of Medicine; St. Louis Missouri
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology; University of Padua; Padua Italy
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32
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Gastroesophageal reflux disease-related and functional heartburn: pathophysiology and treatment. Curr Opin Gastroenterol 2016; 32:344-52. [PMID: 27206157 DOI: 10.1097/mog.0000000000000282] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Patients who continue to experience heartburn symptoms despite adequate-dose proton pump inhibitor therapy have unmet clinical needs. In this review, we focus on the most recent findings related to the mechanism of heartburn symptom generation, and on the treatment of gastroesophageal reflux disease-related and functional heartburn. RECENT FINDINGS The immunological mechanism in the esophageal mucosa has been addressed as a potential mechanism of the onset of esophageal mucosa damage and the generation of heartburn symptoms. Peripheral or central hypersensitivity in viscera is a potentially unifying pathophysiological concept in functional heartburn. Vonoprazan, a novel and potent first-in-class potassium-competitive acid blocker, is expected to prove useful in the treatment of reflux disease. SUMMARY New findings in the mechanisms of heartburn symptom generation are emerging, including the immunological mediation of esophageal mucosal damage and the development of visceral hypersensitivity in functional heartburn. In the future, we anticipate the emergence of new and specific therapeutic options based on these mechanisms, with less dependence on acid-suppressing agents.
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33
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Banovcin P, Halicka J, Halickova M, Duricek M, Hyrdel R, Tatar M, Kollarik M. Studies on the regulation of transient lower esophageal sphincter relaxations (TLESRs) by acid in the esophagus and stomach. Dis Esophagus 2016; 29:484-9. [PMID: 25873206 DOI: 10.1111/dote.12357] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal reflux, but the regulation of TLESR by stimuli in the esophagus is incompletely understood. We have recently reported that acid infusion in the esophagus substantially (by 75%) increased the number of meal-induced TLESR in healthy subjects. We concluded that the TLESR reflex triggered by gastric distention with meal was enhanced by the stimulation of esophageal nerves by acid. However, the possibilities that the acid infused into the esophagus acts after passing though lower esophageal sphincter in stomach to enhance TLESR, or that the acid directly initiates TLESR from the esophagus were not addressed. Here, we evaluated the effect of acid infusion into the proximal stomach on meal-induced TLESR (study 1) and the ability of acid infusion into the esophagus to initiate TLESR without prior meal (study 2). We analyzed TLESRs by using high-resolution manometry in healthy subjects in paired randomized studies. In study 1, we found that acid infusion into the proximal stomach did not affect TLESRs induced by standard meal. The number of meal-induced TLESRs following the acid infusion into the proximal stomach was similar to the number of meal-induced TLESRs following the control infusion. In study 2, we found that acid infusion into the esophagus without prior meal did not initiate TLESRs. We conclude that the increase in the meal-induced TLESRs by acid in the esophagus demonstrated in our previous study is not attributable to the action of acid in the stomach or to direct initiation of TLESR from the esophagus by acid. Our studies are consistent with the concept that the stimuli in the esophagus can influence TLESRs. The enhancement of TLESR by acid in the esophagus may contribute to pathogenesis of gastroesophageal reflux in some patients.
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Affiliation(s)
- P Banovcin
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia.,Department of Gastroenterology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - J Halicka
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - M Halickova
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - M Duricek
- Department of Gastroenterology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - R Hyrdel
- Department of Gastroenterology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - M Tatar
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia
| | - M Kollarik
- Department of Pathophysiology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia.,Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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34
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Scarpellini E, Ang D, Pauwels A, De Santis A, Vanuytsel T, Tack J. Management of refractory typical GERD symptoms. Nat Rev Gastroenterol Hepatol 2016; 13:281-94. [PMID: 27075264 DOI: 10.1038/nrgastro.2016.50] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The management of patients with refractory GERD (rGERD) is a major clinical challenge for gastroenterologists. In up to 30% of patients with typical GERD symptoms (heartburn and/or regurgitation), acid-suppressive therapy does not provide clinical benefit. In this Review, we discuss the current management algorithm for GERD and the features and management of patients who do not respond to treatment (such as those individuals with an incorrect diagnosis of GERD, inadequate PPI intake, persisting acid reflux and persisting weakly acidic reflux). Symptom response to existing surgical techniques, novel antireflux procedures, and the value of add-on medical therapies (including prokinetics and reflux inhibitors) for rGERD symptoms are discussed. Pharmaceutical agents targeting oesophageal sensitivity, a condition that can contribute to symptom generation in rGERD, are also discussed. Finally, on the basis of available published data and our expert opinion, we present an outline of a current, usable algorithm for management of patients with rGERD that considers the timing and diagnostic use of pH-impedance monitoring on or off PPI, additional diagnostic tests, the clinical use of baclofen and the use of add-on neuromodulators (tricyclic agents and selective serotonin reuptake inhibitors).
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Affiliation(s)
- Emidio Scarpellini
- Translational Research in Gastrointestinal Disorders (TARGID), University of Leuven, Herestraat 49, B-3000 Leuven, Belgium.,Division Gastroenterology, Sapienza University of Rome, Viale del Policlinico 155, 00100, Rome, Italy
| | - Daphne Ang
- Division of Gastroenterology, Changi General Hospital, 2 Simei Street 3, Singapore 529889
| | - Ans Pauwels
- Translational Research in Gastrointestinal Disorders (TARGID), University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
| | - Adriano De Santis
- Division of Gastroenterology, Changi General Hospital, 2 Simei Street 3, Singapore 529889
| | - Tim Vanuytsel
- Translational Research in Gastrointestinal Disorders (TARGID), University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
| | - Jan Tack
- Translational Research in Gastrointestinal Disorders (TARGID), University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
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Abstract
Gastroesophageal reflux disease is one of the commonest chronic conditions in the western world and its prevalence is increasing worldwide. The discovery of the acid pocket explained the paradox of acid reflux occurring more frequently in the postprandial period despite intragastric acidity being low due to the buffering effect of the meal. The acid pocket was first described in 2001 when it was detected as an area of low pH immediately distal to the cardia using dual pH electrode pull-through studies 15 minutes after a meal. It was hypothesized that there was a local pocket of acid close to the gastroesophageal junction that escapes the buffering effect of the meal, and that this is the source of postprandial acidic reflux. The presence of the acid pocket has been confirmed in other studies using different techniques including high-resolution pHmetry, Bravo capsule, magnetic resonance imaging, and scintigraphy. This review aims to describe what we know about the acid pocket including its length, volume, fluid constituents, and its relationship to the lower esophageal sphincter and squamocolumnar junction. We will discuss the possible mechanisms that lead to the formation of the acid pocket and examine what differences exist in patients who suffer from acid reflux. Treatments for reflux disease that affect the acid pocket will also be discussed.
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Xu X, Yu L, Chen Q, Lv H, Qiu Z. Diagnosis and treatment of patients with nonacid gastroesophageal reflux-induced chronic cough. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2016; 20:885-92. [PMID: 26759577 PMCID: PMC4696375 DOI: 10.4103/1735-1995.170625] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gastroesophageal reflux (GER) is one of the most common causes of chronic cough, and chronic cough due to GER represents a subtype of GER-related diseases. Gastroesophageal reflux-induced chronic cough (GERC) can be divided into two subgroups based on the pH of the GER. Nonacid GERC is less common than acid GERC, and its diagnosis and treatment strategy have not been standardized. However, nonacid GERC usually presents with its unique set of characteristics and features upon diagnosis and treatment in the clinic. Although the underlying molecular mechanism of nonacid GERC is not fully understood, it is considered to be associated with reflux theory, reflex theory and airway hypersensitivity. Multi-channel intraluminal impedance combined with pH monitoring is a promising new technique that can detect both acid and nonacid reflux, and our findings as well as those of others have shown its usefulness in diagnosing nonacid GERC. Development of new diagnostic techniques has led to an increased rate of nonacid GERC diagnosis. We summarize our experience in the diagnosis and treatment of nonacid GERC and provide a guide for future therapeutic approaches.
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Affiliation(s)
- Xianghuai Xu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Li Yu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Qiang Chen
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Hanjing Lv
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Zhongmin Qiu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
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Abstract
Eructation is composed of three independent phases: gas escape, upper barrier elimination, and gas transport phases. The gas escape phase is the gastro-LES inhibitory reflex that causes transient relaxation of the lower esophageal sphincter, which is activated by distension of stretch receptors of the proximal stomach. The upper barrier elimination phase is the transient relaxation of the upper esophageal sphincter along with airway protection. This phase is activated by stimulation of rapidly adapting mechanoreceptors of the esophageal mucosa. The gas transport phase is esophageal reverse peristalsis mediated by elementary reflexes, and it is theorized that this phase is activated by serosal rapidly adapting tension receptors. Alteration of the receptors which activate the upper barrier elimination phase of eructation by gastro-esophageal reflux of acid may in part contribute to the development of supra-esophageal reflux disease.
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Refractory chronic cough due to gastroesophageal reflux: Definition, mechanism and management. World J Methodol 2015; 5:149-56. [PMID: 26413488 PMCID: PMC4572028 DOI: 10.5662/wjm.v5.i3.149] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/06/2015] [Accepted: 07/11/2015] [Indexed: 02/06/2023] Open
Abstract
Refractory chronic cough due to gastroesophageal reflux is a troublesome condition unresponsive to the standard medical anti-reflux therapy. Its underlying mechanisms may include incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations and esophageal hypersensitivity. The diagnosis of this disorder depends on both the findings of multi-channel intraluminal impedance-pH monitoring and the subsequent intensified anti-reflux therapy. The strategies of pharmacological treatment for refractory chronic cough due to reflux include the optimization of proton pump inhibitors and add-on therapies with histamine H2 receptor antagonists, baclofen and gabapentin. However, the further study is needed to satisfy its management.
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Scarpellini E, Boecxstaens V, Farré R, Bisschops R, Dewulf D, Gasbarrini A, Pauwels A, Blondeau K, Tack J. Effect of baclofen on the acid pocket at the gastroesophageal junction. Dis Esophagus 2015; 28:488-95. [PMID: 24758736 DOI: 10.1111/dote.12224] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Previous studies established that a pocket of highly acidic gastric juice is present postprandially at the gastroesophageal junction in man. The GABA-B agonist baclofen inhibits postprandial reflux events through its effects on the lower esophageal sphincter (LES). The aim of the current study was to investigate whether baclofen would affect the location and the extent of the postprandial acid pocket in healthy volunteers. Twelve healthy volunteers underwent acid pocket studies on two different occasions, at least 1 week apart. LES position was determined preprandially with pull-through manometry. Dual pH electrode and manometry probe stepwise pull-through (1 cm/minute, LES-10 to +5 cm) was performed at 30-minute intervals for 150 minutes, with administration of placebo or baclofen 40 mg after the first and ingestion of a liquid meal after the second pull-through. After placebo, a significant drop in intragastric gastric pH was present at the gastroesophageal junction after the meal, reflecting the acid pocket, and this was associated with a drop in LES pressure. Baclofen did not affect the presence of the acid pocket, but prevented the postprandial drop in LES pressure, and the extent of the acid pocket above the upper margin of the manometrically located LES was significantly decreased by baclofen (1.6 ± 0.7 vs. 0.3 ± 0.4 cm at 60 minutes, 2.2 ± 0.6 vs. 0.2 ± 0.6 at 90 minutes, and 1.5 ± 0.5 vs. 0.7 ± 0.7 cm at 120 minutes, all P < 0.05). Baclofen does not alter the intragastric acid pocket, but limits its extension into the distal esophagus, probably through an increase in postprandial LES pressure.
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Affiliation(s)
- E Scarpellini
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - V Boecxstaens
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - R Farré
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - R Bisschops
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - D Dewulf
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - A Gasbarrini
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - A Pauwels
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - K Blondeau
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - J Tack
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
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Boeckxstaens G, El-Serag HB, Smout AJPM, Kahrilas PJ. Republished: symptomatic reflux disease: the present, the past and the future. Postgrad Med J 2015; 91:46-54. [PMID: 25583739 PMCID: PMC4316838 DOI: 10.1136/postgradmedj-2013-306393rep] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The worldwide incidence of GORD and its complications is increasing along with the exponentially increasing problem of obesity. Of particular concern is the relationship between central adiposity and GORD complications, including oesophageal adenocarcinoma. Driven by progressive insight into the epidemiology and pathophysiology of GORD, the earlier belief that increased gastroesophageal reflux mainly results from one dominant mechanism has been replaced by acceptance that GORD is multifactorial. Instigating factors, such as obesity, age, genetics, pregnancy and trauma may all contribute to mechanical impairment of the oesophagogastric junction resulting in pathological reflux and accompanying syndromes. Progression of the disease by exacerbating and perpetuating factors such as obesity, neuromuscular dysfunction and oesophageal fibrosis ultimately lead to development of an overt hiatal hernia. The latter is now accepted as a central player, impacting on most mechanisms underlying gastroesophageal reflux (low sphincter pressure, transient lower oesophageal sphincter relaxation, oesophageal clearance and acid pocket position), explaining its association with more severe disease and mucosal damage. Since the introduction of proton pump inhibitors (PPI), clinical management of GORD has markedly changed, shifting the therapeutic challenge from mucosal healing to reduction of PPI-resistant symptoms. In parallel, it became clear that reflux symptoms may result from weakly acidic or non-acid reflux, insight that has triggered the search for new compounds or minimally invasive procedures to reduce all types of reflux. In summary, our view on GORD has evolved enormously compared to that of the past, and without doubt will impact on how to deal with GORD in the future.
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Affiliation(s)
- Guy Boeckxstaens
- Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, KU Leuven, Leuven, Belgium
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | - André J P M Smout
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
| | - Peter J Kahrilas
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Vakil N. Baclofen and transient lower oesophageal sphincter relaxations - the band plays on. Aliment Pharmacol Ther 2014; 40:1360-1. [PMID: 25376198 DOI: 10.1111/apt.12987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 09/22/2014] [Indexed: 12/24/2022]
Affiliation(s)
- N Vakil
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
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43
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Miner PB, Silberg DG, Ruth M, Miller F, Pandolfino J. Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study. BMC Gastroenterol 2014; 14:188. [PMID: 25407279 PMCID: PMC4289246 DOI: 10.1186/1471-230x-14-188] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Accepted: 05/29/2014] [Indexed: 01/09/2023] Open
Abstract
Background The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose–response effect of lesogaberan on reflux episodes in partial responders. Methods In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance–pH measurements were taken. Results Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment. Conclusions Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events. Trial registration ClinicalTrials.gov identifier:
NCT01043185.
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Affiliation(s)
- Philip B Miner
- Oklahoma Foundation for Digestive Research, 535 NW 9th Street, Suite 325, Oklahoma City, OK, USA.
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Curcic J, Schwizer A, Kaufman E, Forras-Kaufman Z, Banerjee S, Roy S, Pal A, Hebbard GS, Boesiger P, Fried M, Steingoetter A, Schwizer W, Fox M. Effects of baclofen on the functional anatomy of the oesophago-gastric junction and proximal stomach in healthy volunteers and patients with GERD assessed by magnetic resonance imaging and high-resolution manometry: a randomised controlled double-blind study. Aliment Pharmacol Ther 2014; 40:1230-40. [PMID: 25230154 DOI: 10.1111/apt.12956] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 05/23/2014] [Accepted: 08/25/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND The mechanism of reflux protection may involve a 'flap valve' at the oesophago-gastric junction (OGJ). AIM To assess the effects of baclofen, a gamma-aminobutyric acid receptor type-B (GABA-B) agonist known to suppress reflux events, on the 'functional anatomy' of the OGJ and proximal stomach after a large test meal. METHODS Twelve healthy volunteers (HVs) and 12 patients with gastro-oesophageal reflux disease (GERD); with erosive oesophagitis or pathological oesophageal acid exposure completed a randomised, double-blind, cross-over study. On 2 test days participants received 40-mg baclofen or placebo before ingestion of a large test meal. OGJ structure and function were assessed by high-resolution manometry (HRM) and magnetic resonance imaging (MRI) using validated methods. Measurements of the oesophago-gastric angle were derived from three-dimensional models reconstructed from anatomic MRI images. Cine-MRI and HRM identified postprandial reflux events. Mixed model analysis and Wilcoxon rank signed tests assessed differences between participant groups and treatment conditions. RESULTS In both HVs and GERD patients, baclofen reduced the frequency of postprandial reflux events. The oesophago-gastric insertion angle in GERD patients was reduced (-4.1 ± 1.8, P = 0.025), but was unchanged in healthy controls. In both study groups, baclofen augmented lower oesophageal sphincter (LES) pressure (HVs: +7.3 ± 1.8 mmHg, P < 0.0001, GERD: +4.50 ± 1.49 mmHg, P < 0.003) and increased LES length (HVs: +0.48 ± 0.11 cm, P < 0.0003, GERD: +0.35 ± 0.06 cm, P < 0.0001). CONCLUSIONS Baclofen inhibits transient LES relaxations and augments LES pressure and length. Additionally, baclofen has effects on the 'functional anatomy' of the OGJ and proximal stomach in GERD patients, which may suppress reflux by means of a 'flap valve' mechanism.
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Affiliation(s)
- J Curcic
- Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland; Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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The effects of baclofen for the treatment of gastroesophageal reflux disease: a meta-analysis of randomized controlled trials. Gastroenterol Res Pract 2014; 2014:307805. [PMID: 25389436 PMCID: PMC4217339 DOI: 10.1155/2014/307805] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 08/08/2014] [Accepted: 08/27/2014] [Indexed: 12/14/2022] Open
Abstract
Objectives. Baclofen can relieve gastroesophageal reflux-related symptoms in healthy subjects and gastroesophageal reflux disease (GERD) patients by reducing the incidence of transient lower esophageal sphincter relaxation. This meta-analysis aimed to evaluate the efficacy and safety of baclofen for the treatment of GERD. Methods. We systematically searched randomized controlled trials published prior to November 2013 from PubMed, Medline, Embase, ScienceDirect, ClinicalTrials.gov, and the Cochrane Central Register of Randomized Controlled Trials. We performed a meta-analysis of all eligible trials. Results. Nine studies were identified with a total of 283 GERD patients and healthy subjects. Comparative analysis provided high quality data supporting the ability of baclofen to promote a short-term decrease in the number of reflux episodes per patient, the average length of reflux episodes, and the incidence of transient lower esophageal sphincter relaxation. No serious adverse events or death events were reported, and there were no significant differences in the overall adverse events between baclofen and placebo. All reported side effects of baclofen were of mild-to-moderate intensity, and the drug was well tolerated. Conclusion. Abundant evidence suggests that baclofen may be a useful approach for the treatment of GERD patients; however, a larger well-designed research study would further confirm this recommendation.
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Halicka J, Banovcin P, Halickova M, Demeter M, Hyrdel R, Tatar M, Kollarik M. Acid infusion into the esophagus increases the number of meal-induced transient lower esophageal sphincter relaxations (TLESRs) in healthy volunteers. Neurogastroenterol Motil 2014; 26:1469-76. [PMID: 25155416 PMCID: PMC4177286 DOI: 10.1111/nmo.12409] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 07/15/2014] [Indexed: 01/06/2023]
Abstract
BACKGROUND Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal reflux (GER) but the regulation of TLESR by stimuli in the esophagus is incompletely understood. If stimuli in the esophagus can influence TLESR, then such regulation may perpetuate or limit GER. We addressed the hypothesis that acid in the esophagus enhances TLESRs. METHODS We evaluated the effect of acid infusion into the distal esophagus on TLESRs evoked by a standard meal in a paired randomized study in healthy subjects. TLESRs were evaluated by using high resolution manometry (HRM). KEY RESULTS We found that acid in the esophagus enhanced meal-induced TLESRs. Compared to control infusion the number of TLESRs (median [interquartile range]) was increased during 2 h following the acid infusion (11 [9-14] vs 17 [12.5-20], p < 0.01). The average duration of individual TLESRs was not affected. The time-course analysis revealed that a robust increase in TLESRs occurred already in the first hour when the number of TLESRs nearly doubled (6 [5.5-7.5] vs 11 [7.5-12.5], p < 0.05). In contrast to the enhancement of TLESRs, the number of swallows was not changed. CONCLUSIONS & INFERENCES The acid infusion into the esophagus increases the number of meal-induced TLESRs in healthy subjects. Our results provide evidence for the concept that the stimuli in the esophagus can influence TLESRs. The regulation of TLESR by stimuli in the esophagus may contribute to pathogenesis of GER in some patients.
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Affiliation(s)
- J Halicka
- Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia
| | - P Banovcin
- Department of Gastroenterology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia
| | - M Halickova
- Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia
| | - M Demeter
- Department of Gastroenterology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia
| | - R Hyrdel
- Department of Gastroenterology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia
| | - M Tatar
- Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia
| | - M Kollarik
- Department of Pathophysiology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Slovakia,Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, USA
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Kessing BF, Bredenoord AJ, Smout AJPM. The pathophysiology, diagnosis and treatment of excessive belching symptoms. Am J Gastroenterol 2014; 109:1196-203); (Quiz) 1204. [PMID: 25001253 DOI: 10.1038/ajg.2014.165] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 04/18/2014] [Indexed: 12/11/2022]
Abstract
Excessive belching is a commonly observed complaint in clinical practice that can occur not only as an isolated symptom but also as a concomitant symptom in patients with gastroesophageal reflux disease (GERD) or functional dyspepsia. Impedance monitoring has revealed that there are two mechanisms through which belching can occur: the gastric belch and the supragastric belch. The gastric belch is the result of a vagally mediated reflex leading to relaxation of the lower esophageal sphincter and venting of gastric air. The supragastric belch is a behavioral peculiarity. During this type of belch, pharyngeal air is sucked or injected into the esophagus, after which it is immediately expulsed before it has reached the stomach. Patients who belch excessively invariably exhibit an increased incidence of supragastric, not of gastric belches. Moreover, supragastric belches can elicit regurgitation episodes in patients with the rumination syndrome and sometimes appear to induce reflux episodes as well. Behavioral therapy has been proven to decrease belching complaints in patients with isolated excessive belching, but its effect is unknown in frequently belching patients with GERD, functional dyspepsia or rumination.
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Affiliation(s)
- Boudewijn F Kessing
- Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Albert J Bredenoord
- Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
| | - André J P M Smout
- Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
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Abstract
PURPOSE OF REVIEW In the last decade, with the advent of new oesophageal testing [i.e. 24-h impedance-pH monitoring, combined impedance-manometry, high-resolution manometry (HRM)], relevant progress in understanding the mechanisms contributing to the development of gastro-oesophageal reflux disease (GORD) has been made, allowing a better management of patients with this disorder. The aim of our review is to report the state-of-the-art about oesophageal motor disorders in patients with reflux disease and to stimulate new research in this field. RECENT FINDINGS Hypotensive lower oesophageal sphincter (LOS), transient LOS relaxations, impairment of oesophagogastric junction including hiatal hernia, oesophageal bolus transit abnormalities and presence of ineffective oesophageal motility have been strongly implicated in GORD development. In particular, the majority of recent studies carried out with HRM and impedance-pH testing reported that these motor abnormalities are increasingly prevalent with increasing severity of GORD, from nonerosive reflux disease and erosive oesophagitis to Barrett's oesophagus. SUMMARY Defining and characterizing oesophageal dysmotility in patients with reflux disease is of maximum importance in order to properly diagnose these patients and to treat them with the best management of care. New studies are needed in order to better understand the physiomechanic basis of oesophageal dysmotility in GORD patients.
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49
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Abstract
The worldwide incidence of GORD and its complications is increasing along with the exponentially increasing problem of obesity. Of particular concern is the relationship between central adiposity and GORD complications, including oesophageal adenocarcinoma. Driven by progressive insight into the epidemiology and pathophysiology of GORD, the earlier belief that increased gastroesophageal reflux mainly results from one dominant mechanism has been replaced by acceptance that GORD is multifactorial. Instigating factors, such as obesity, age, genetics, pregnancy and trauma may all contribute to mechanical impairment of the oesophagogastric junction resulting in pathological reflux and accompanying syndromes. Progression of the disease by exacerbating and perpetuating factors such as obesity, neuromuscular dysfunction and oesophageal fibrosis ultimately lead to development of an overt hiatal hernia. The latter is now accepted as a central player, impacting on most mechanisms underlying gastroesophageal reflux (low sphincter pressure, transient lower oesophageal sphincter relaxation, oesophageal clearance and acid pocket position), explaining its association with more severe disease and mucosal damage. Since the introduction of proton pump inhibitors (PPI), clinical management of GORD has markedly changed, shifting the therapeutic challenge from mucosal healing to reduction of PPI-resistant symptoms. In parallel, it became clear that reflux symptoms may result from weakly acidic or non-acid reflux, insight that has triggered the search for new compounds or minimally invasive procedures to reduce all types of reflux. In summary, our view on GORD has evolved enormously compared to that of the past, and without doubt will impact on how to deal with GORD in the future.
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Affiliation(s)
- Guy Boeckxstaens
- Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, KU Leuven, Leuven, Belgium
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | - André J P M Smout
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
| | - Peter J Kahrilas
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Sigfridsson K, Andersson T, Berntsson V, Wang Y. A small structural change resulting in improved properties for product development. Drug Dev Ind Pharm 2014; 41:866-73. [DOI: 10.3109/03639045.2014.911307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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