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Nisr RB, Shah DS, Hundal HS. EP4: A prostanoid receptor that modulates insulin signalling in rat skeletal muscle cells. Cell Signal 2025; 126:111516. [PMID: 39592018 DOI: 10.1016/j.cellsig.2024.111516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 11/14/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024]
Abstract
The EP4 (prostaglandin E2) receptor plays a crucial role in myogenesis and skeletal muscle regeneration, yet its involvement in regulating insulin-dependent metabolic pathways is not well characterised. Our research investigates the expression of EP4 in rat skeletal L6 myotubes and its impact on insulin signalling. We found that activation of EP4 by selective agonists disrupts insulin signalling and insulin-stimulated glucose uptake. This impairment is associated with enhanced pro-inflammatory NF-κB signalling, a process that can be attenuated by EP4 antagonists. Importantly, EP4 antagonism also reduces NF-κB activation induced by palmitate and the associated reduction in insulin signalling, an effect not replicated by antagonists of EP1, EP2, or EP3 receptors. These observations indicate that the EP4 receptor is a modulator of insulin action and that it contributes to fatty-acid-induced insulin resistance in skeletal muscle cells. Our findings suggest that EP4 could be a potential therapeutic target for managing insulin resistance.
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Affiliation(s)
- Raid B Nisr
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Dinesh S Shah
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Harinder S Hundal
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
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Lashen SA. Response to Letter to the Editor: "Same condition treated with the same drug in the same daily dose but a different response-Why?". J Pediatr Gastroenterol Nutr 2024; 78:1415-1416. [PMID: 38594818 DOI: 10.1002/jpn3.12209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 03/20/2024] [Indexed: 04/11/2024]
Affiliation(s)
- Sameh A Lashen
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Biniszewska O, Jacenik D, Tarasiuk A, Fichna J. Current and future pharmacotherapies for the management of constipation-predominant irritable bowel syndrome. Expert Opin Pharmacother 2024; 25:1039-1049. [PMID: 38856704 DOI: 10.1080/14656566.2024.2366993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 06/07/2024] [Indexed: 06/11/2024]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a common gastrointestinal disorder affecting 9-23% of the world's population, with a higher prevalence among women. IBS is a complex disorder influenced by psychosocial, physiological, and genetic factors, exacerbated by stress. AREAS COVERED Research confirms that the most common subtype of IBS is IBS-C. Therefore, new therapies are being developed to speed up bowel movement and reduce constipation, with drugs such as linaclotide, plecanatide, lubiprostone, or tegaserod available to reduce IBS-C symptoms. In addition, patients' condition is improved by foods rich in fiber and low in FODMAP and the use of biotics. EXPERT OPINION The topic is of great importance due to the growing number of patients suffering from IBS-C and its significant impact on quality of life. Current clinical trials of new therapeutic options are not too successful, and it seems that one of the plausible treatment options could be the multi-drug cocktail with some, or perhaps even all its ingredients emerging from drug re-purposing. Another important path that needs to be explored further in IBS-C patients is the adjustment of dietary habits and/or introduction of dietary or nutritional intervention.
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Affiliation(s)
- Olga Biniszewska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland
| | - Aleksandra Tarasiuk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Shaughnessy CA, Yadav S, Bratcher PE, Zeitlin PL. Receptor-mediated activation of CFTR via prostaglandin signaling pathways in the airway. Am J Physiol Lung Cell Mol Physiol 2022; 322:L305-L314. [PMID: 35020527 PMCID: PMC8858663 DOI: 10.1152/ajplung.00388.2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Cystic fibrosis (CF) is a genetic disease caused by mutations of the gene encoding a cAMP-activated Cl- channel, the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR modulator therapies consist of small-molecule drugs that rescue mutant CFTR. Regimens of single or combinations of CFTR modulators still rely on endogenous levels of cAMP to regulate CFTR activity. We investigated CFTR activation by the natural mediator prostaglandin E2 (PGE2) and lubiprostone (a Food and Drug Administration-approved drug known to target prostaglandin receptors) and tested the hypothesis that receptor-mediated CFTR activators can be used in combination with currently available CFTR modulators to increase function of mutant CFTR. Primary-cultured airway epithelia were assayed in Ussing chambers. Experimental CFTR activators and established CFTR modulators were applied for 24 h and/or acutely and analyzed for their effect on CFTR activity as measured by changes in short-circuit current (ISC). In non-CF airway epithelia, acute application of lubiprostone and PGE2 activated CFTR to the levels comparable to forskolin (Fsk). Pretreatment (24 h) with antagonists to prostaglandin receptors EP2 and EP4 abolished the ability of lubiprostone to acutely activate CFTR. In F508del homozygous airway epithelia pretreated with the triple combination of elexacaftor, tezacaftor, and ivacaftor (ELEXA/TEZ/IVA; i.e., Trikafta), acute application of lubiprostone was able to maximally activate CFTR. Prolonged (24 h) cotreatment of F508del homozygous epithelia with ELEXA/TEZ/IVA and lubiprostone increased acute CFTR activation by ∼60% compared with the treatment with ELEXA/TEZ/IVA alone. This work establishes the feasibility of targeting prostaglandin receptors to activate CFTR on the airway epithelia and demonstrates that cotreatment with lubiprostone can further restore modulator-rescued CFTR.
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Affiliation(s)
| | - Sangya Yadav
- 1Department of Pediatrics, National Jewish Health, Denver, Colorado
| | - Preston E. Bratcher
- 1Department of Pediatrics, National Jewish Health, Denver, Colorado,2Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado
| | - Pamela L. Zeitlin
- 1Department of Pediatrics, National Jewish Health, Denver, Colorado,2Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado
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Sharma A, Rao SSC, Kearns K, Orleck KD, Waldman SA. Review article: diagnosis, management and patient perspectives of the spectrum of constipation disorders. Aliment Pharmacol Ther 2021; 53:1250-1267. [PMID: 33909919 PMCID: PMC8252518 DOI: 10.1111/apt.16369] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/24/2020] [Accepted: 03/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic constipation is a common, heterogeneous disorder with multiple symptoms and pathophysiological mechanisms. Patients are often referred to a gastroenterology provider after laxatives fail. However, there is limited knowledge of the spectrum and management of constipation disorders. AIM To discuss the latest understanding of the spectrum of constipation disorders, tools for identifying a pathophysiologic-based diagnosis in the specialist setting, treatment options and the patient's perspective of constipation. METHODS Literature searches were conducted using PubMed for constipation diagnostic criteria, diagnostic tools and approved treatments. The authors provided insight from their own practices. RESULTS Clinical assessment, stool diaries and Rome IV diagnostic criteria can facilitate diagnosis, evaluate severity and distinguish between IBS with constipation, chronic idiopathic constipation and dyssynergic defecation. Novel smartphone applications can help track constipation symptoms. Rectal examinations, anorectal manometry and balloon expulsion, assessments of neuromuscular function with colonic transit time and colonic manometry can provide mechanistic understanding of underlying pathophysiology. Treatments include lifestyle and diet changes, biofeedback therapy and pharmacological agents. Several classes of laxatives, as well as prokinetic and prosecretory agents, are available; here we describe their mechanisms of action, efficacy and side effects. CONCLUSIONS Constipation includes multiple overlapping subtypes identifiable using detailed history, current diagnostic tools and smartphone applications. Recognition of individual subtype(s) could pave the way for optimal, evidence-based treatments by a gastroenterology provider.
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Affiliation(s)
- Amol Sharma
- Division of Gastroenterology/HepatologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | - Satish S. C. Rao
- Division of Gastroenterology/HepatologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | | | | | - Scott A. Waldman
- Department of Pharmacology and Experimental TherapeuticsThomas Jefferson UniversityPhiladelphiaPAUSA
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Tan Q, di Stefano G, Tan X, Renjie X, Römermann D, Talbot SR, Seidler UE. Inhibition of Na + /H + exchanger isoform 3 improves gut fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator-deficient and F508del mutant mice. Br J Pharmacol 2021; 178:1018-1036. [PMID: 33179259 DOI: 10.1111/bph.15323] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 11/01/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Constipation and intestinal obstructive episodes are major health problems in cystic fibrosis (CF) patients. Three FDA-approved drugs against constipation-prone irritable bowel syndrome were tested for their ability to increase luminal fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator (CFTR) null (cftr-/- ) and F508del mutant (F508delmut/mut ) murine intestine. EXPERIMENTAL APPROACH Guanylate cyclase C agonist linaclotide, PGE1 analogue lubiprostone and intestine-specific NHE3 inhibitor tenapanor were perfused through a ~3 cm jejunal, proximal or mid-distal colonic segment in anaesthetized cftr-/- , F508delmut/mut and WT mice. Net fluid balance was determined gravimetrically and alkaline output by pH-stat back titration. KEY RESULTS Basal jejunal fluid absorptive rates were significantly higher and basal HCO3 - output was significantly lower in cftr-/- and F508delmut/mut compared to WT mice. In cftr-/- and F508delmut/mut mice, all three drugs significantly inhibited the fluid absorptive rate and increased alkaline output in the jejunum and tenapanor and lubiprostone, but not linaclotide, in the colon. After tenapanor pre-incubation, linaclotide elicited a robust fluid secretory response in WT jejunum, while no further change in absorptive rates was observed in cftr-/- and F508delmut/mut jejunum, suggesting that the increase in gut fluidity and alkalinity by linaclotide in CF gut is mediated via NHE3 inhibition. Lubiprostone also inhibited fluid absorption in cftr-/- and F508delmut/mut jejunum via NHE3 inhibition but had a residual NHE3-independent effect. CONCLUSION AND IMPLICATIONS Linaclotide, lubiprostone and tenapanor reduced fluid absorption and increased alkaline output in the CF gut. Their application may ameliorate constipation and reduce obstructive episodes in CF patients.
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Affiliation(s)
- Qinghai Tan
- Department of Gastroenterology, Hannover Medical School, Hanover, Germany
| | | | - Xinjie Tan
- Department of Gastroenterology, Hannover Medical School, Hanover, Germany
| | - Xiu Renjie
- Department of Gastroenterology, Hannover Medical School, Hanover, Germany
| | - Dorothee Römermann
- Department of Gastroenterology, Hannover Medical School, Hanover, Germany
| | - Steven R Talbot
- Institute of Veterinary Research, Hannover Medical School, Hanover, Germany
| | - Ursula E Seidler
- Department of Gastroenterology, Hannover Medical School, Hanover, Germany
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Heeney A, Rogers AC, Mohan H, Mc Dermott F, Baird AW, Winter DC. Prostaglandin E 2 receptors and their role in gastrointestinal motility - Potential therapeutic targets. Prostaglandins Other Lipid Mediat 2021; 152:106499. [PMID: 33035691 DOI: 10.1016/j.prostaglandins.2020.106499] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 07/20/2020] [Accepted: 10/01/2020] [Indexed: 12/19/2022]
Abstract
Prostaglandin E2 (PGE2) is found throughout the gastrointestinal tract in a diverse variety of functions and roles. The recent discovery of four PGE2 receptor subtypes in intestinal muscle layers as well as in the enteric plexus has led to much interest in the study of their roles in gut motility. Gut dysmotility has been implicated in functional disease processes including irritable bowel syndrome (IBS) and slow transit constipation, and lubiprostone, a PGE2 derivative, has recently been licensed to treat both conditions. The diversity of actions of PGE2 in the intestinal tract is attributed to its differing effects on its downstream receptor types, as well as their varied distribution in the gut, in both health and disease. This review aims to identify the role and distribution of PGE2 receptors in the intestinal tract, and aims to elucidate their distinct role in gut motor function, with a specific focus on functional intestinal pathologies.
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Affiliation(s)
- A Heeney
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
| | - A C Rogers
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - H Mohan
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - F Mc Dermott
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland
| | - A W Baird
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland
| | - D C Winter
- Institute for Clinical Outcomes, Research and Education (ICORE), St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
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Norel X, Sugimoto Y, Ozen G, Abdelazeem H, Amgoud Y, Bouhadoun A, Bassiouni W, Goepp M, Mani S, Manikpurage HD, Senbel A, Longrois D, Heinemann A, Yao C, Clapp LH. International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E 2 Receptors (EP1-4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions. Pharmacol Rev 2020; 72:910-968. [PMID: 32962984 PMCID: PMC7509579 DOI: 10.1124/pr.120.019331] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.
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Affiliation(s)
- Xavier Norel
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Yukihiko Sugimoto
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Gulsev Ozen
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Heba Abdelazeem
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Yasmine Amgoud
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Amel Bouhadoun
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Wesam Bassiouni
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Marie Goepp
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Salma Mani
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Hasanga D Manikpurage
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Amira Senbel
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Dan Longrois
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Akos Heinemann
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Chengcan Yao
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
| | - Lucie H Clapp
- Université de Paris, Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S 1148, CHU X. Bichat, Paris, France (X.N., G.O., H.A., Y.A., A.B., S.M., H.D.M., A.S., D.L.); Université Sorbonne Paris Nord, Villetaneuse, France (X.N., H.A., Y.A., A.B., S.M., D.L.); Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan (Y.S.); Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey (G.O.); Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt (A.S., H.A., W.B.); Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom (C.Y., M.G.); Institut Supérieur de Biotechnologie de Monastir (ISBM), Université de Monastir, Monastir, Tunisia (S.M.); CHU X. Bichat, AP-HP, Paris, France (D.L.); Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria (A.H.); and Centre for Cardiovascular Physiology & Pharmacology, University College London, London, United Kingdom (L.H.C.)
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9
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Straface M, Makwana R, Palmer A, Rombolà L, Aleong JC, Morrone LA, Sanger GJ. Inhibition of Neuromuscular Contractions of Human and Rat Colon by Bergamot Essential Oil and Linalool: Evidence to Support a Therapeutic Action. Nutrients 2020; 12:nu12051381. [PMID: 32408669 PMCID: PMC7284490 DOI: 10.3390/nu12051381] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/06/2020] [Accepted: 05/09/2020] [Indexed: 12/20/2022] Open
Abstract
Bergamot essential oil (BEO) added to food and drink promotes a citrus flavour. Folklore suggests benefits on gastrointestinal functions but with little supporting evidence. BEO and major constituents (linalool, limonene, linalyl acetate) were therefore examined for any ability to influence neuromuscular contractions of human and rat colon. Circular muscle strips (macroscopically-normal human colon obtained following ethical approval at cancer surgery; Sprague-Dawley rats) were suspended in baths (Krebs solution; 37 °C; 5% CO2 in O2) for measurement of neuronally-mediated contractions (prevented by tetrodotoxin or atropine) evoked by electrical field stimulation (5 Hz, 0.5 ms pulse width, 10s/minute, maximally-effective voltage), or contractions evoked by KCl (submaximally-effective concentrations). BEO and each constituent concentration dependently inhibited neuronally-mediated and KCl-induced contractions. In human: apparent pIC50 for BEO (volume/volume Krebs), respectively, 3.8 ± 0.3 and 4.4 ± 0.3; Imax 55.8% ± 4.2% and 37.5% ± 4.2%. For the constituents, the rank order of potency differed in human (linalool > limonene >> linalyl-acetate) and rat colon (linalyl-acetate > limonene = linalool), but rank order of efficacy was similar (linalool >> (BEO) = linalyl-acetate >> limonene). Thus, linalool had high efficacy but greater potency in human colon (Imax 76.8% ± 6.9%; pIC50 6.7 ± 0.2; n = 4) compared with rat colon (Imax 75.3% ± 1.9%; pIC50 5.8 ± 0.1; n = 4). The ability of BEO and linalool to inhibit human colon neuromuscular contractility provides a mechanism for use as complementary treatments of intestinal disorders.
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Affiliation(s)
- Marilisa Straface
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health Science and Nutrition, University of Calabria, 87036 Rende, Italy; (M.S.); (L.R.); (L.A.M.)
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK; (R.M.); (A.P.)
| | - Raj Makwana
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK; (R.M.); (A.P.)
| | - Alexandra Palmer
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK; (R.M.); (A.P.)
| | - Laura Rombolà
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health Science and Nutrition, University of Calabria, 87036 Rende, Italy; (M.S.); (L.R.); (L.A.M.)
| | - Joanne Chin Aleong
- Department of Pathology, Royal London Hospital, Barts Health NHS Trust, London E1 1BB, UK;
| | - Luigi Antonio Morrone
- Preclinical and Translational Pharmacology, Department of Pharmacy, Health Science and Nutrition, University of Calabria, 87036 Rende, Italy; (M.S.); (L.R.); (L.A.M.)
| | - Gareth J. Sanger
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK; (R.M.); (A.P.)
- Correspondence: ; Tel.: +44-(0)-207-882-6027
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10
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Vriesman MH, Koppen IJN, Camilleri M, Di Lorenzo C, Benninga MA. Management of functional constipation in children and adults. Nat Rev Gastroenterol Hepatol 2020; 17:21-39. [PMID: 31690829 DOI: 10.1038/s41575-019-0222-y] [Citation(s) in RCA: 240] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/26/2019] [Indexed: 02/06/2023]
Abstract
Functional constipation is common in children and adults worldwide. Functional constipation shows similarities in children and adults, but important differences also exist regarding epidemiology, symptomatology, pathophysiology, diagnostic workup and therapeutic management. In children, the approach focuses on the behavioural nature of the disorder and the initial therapeutic steps involve toilet training and laxatives. In adults, management focuses on excluding an underlying cause and differentiating between different subtypes of functional constipation - normal transit, slow transit or an evacuation disorder - which has important therapeutic consequences. Treatment of adult functional constipation involves lifestyle interventions, pelvic floor interventions (in the presence of a rectal evacuation disorder) and pharmacological therapy. When conventional treatments fail, children and adults are considered to have intractable functional constipation, a troublesome and distressing condition. Intractable constipation is managed with a stepwise approach and in rare cases requires surgical interventions such as antegrade continence enemas in children or colectomy procedures for adults. New drugs, including prokinetic and prosecretory agents, and surgical strategies, such as sacral nerve stimulation, have the potential to improve the management of children and adults with intractable functional constipation.
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Affiliation(s)
- Mana H Vriesman
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
| | - Ilan J N Koppen
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Michael Camilleri
- C.E.N.T.E.R. Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Carlo Di Lorenzo
- Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | - Marc A Benninga
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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11
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Pustovit RV, Itomi Y, Ringuet M, Diwakarla S, Chai XY, McQuade RM, Tsukimi Y, Furness JB. Muscarinic receptor 1 allosteric modulators stimulate colorectal emptying in dog, mouse and rat and resolve constipation. Neurogastroenterol Motil 2019; 31:e13692. [PMID: 31374156 DOI: 10.1111/nmo.13692] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Accepted: 07/19/2019] [Indexed: 01/15/2023]
Abstract
BACKGROUND Because M1 muscarinic receptors are expressed by enteric neurons, we investigated whether positive allosteric modulators of these receptors (M1PAMs) would enhance colorectal propulsion and defecation in dogs, mice, and rats. METHODS The potencies of the M1PAMs, T662 or T523, were investigated using M1 receptor-expressing CHO cells. Effectiveness of M1PAMs on defecation was investigated by oral administration in mice and rats, by recording propulsive contractions in anaesthetized rats and by recording high amplitude propagating contractions in dogs. KEY RESULTS PAM EC50 values in M1 receptor-expressing CHO cells were 0.7-1.8 nmol/L for T662 and 8-10 nmol/L for T523. The compounds had 1000-fold lower potencies as agonists. In anesthetized rats, both compounds elicited propulsive colorectal contractions, and in dogs, mice, and rats, oral administration increased fecal output. No adverse effects were observed in conscious animals. M1PAMs triggered propagated high amplitude contractions and caused defecation in dogs. Nerve-mediated contractions were enhanced in the isolated mouse colon. M1PAMs were equi-effective in rats with or without the pelvic nerves being severed. In two models of constipation in mice, opiate-induced constipation and constipation of aging, defecation was induced and constipation was reversed. CONCLUSION AND INFERENCES M1PAMs act at targets sites in the colorectum to enhance colorectal propulsion. They are effective across species, and they reverse experimentally induced constipation. Previous studies have shown that they are safe in human. Because they provide an enhancement of physiological control rather than being direct agonists, they are predicted to provide effective treatment for constipation.
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Affiliation(s)
- Ruslan V Pustovit
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Yasuo Itomi
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Mitchell Ringuet
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Shanti Diwakarla
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Xin-Yi Chai
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Rachel M McQuade
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
| | - Yasuhiro Tsukimi
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - John B Furness
- Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.,Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Vic., Australia
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12
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Arakawa K, Ishigami T, Nakai-Sugiyama M, Chen L, Doi H, Kino T, Minegishi S, Saigoh-Teranaka S, Sasaki-Nakashima R, Hibi K, Kimura K, Tamura K. Lubiprostone as a potential therapeutic agent to improve intestinal permeability and prevent the development of atherosclerosis in apolipoprotein E-deficient mice. PLoS One 2019; 14:e0218096. [PMID: 31206525 PMCID: PMC6576757 DOI: 10.1371/journal.pone.0218096] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/24/2019] [Indexed: 12/17/2022] Open
Abstract
The interaction between atherosclerosis and commensal microbes through leaky gut syndrome (LGS), which is characterized by impaired intestinal permeability and the introduction of undesired pathogens into the body, has not been fully elucidated. Our aim was to investigate the potential role of a ClC-2 chloride channel activator, lubiprostone, which is reported to have beneficial effects on LGS, in the development of atherosclerosis in apolipoprotein E–deficient (ApoE-/-) mice. After a 15-week feeding period of a Western diet (WD), ApoE-/- mice were treated with a Western-type diet (WD) alone or WD with oral supplementation of lubiprostone for 10 weeks. This feeding protocol was followed by experimental evaluation of LGS and atherosclerotic lesions in the aorta. In mice with lubiprostone, in vivo translocation of orally administered 4-kDa FITC-dextran was significantly improved, and RNA expression of the epithelial tight junction proteins, Zo-1 and occludin, was significantly up-regulated in the ileum, compared to the WD alone group, suggesting a possible reversal of WD-induced intestinal barrier dysfunction. As a result, WD-induced exacerbation of atherosclerotic lesion formation was reduced by 69% in longitudinally opened aortas and 26% in aortic root regions. In addition, there was a significant decrease in circulating immunoglobulin level, followed by an attenuation of inflammatory responses in the perivascular adipose tissue, as evidenced by reduced expression of pro-inflammatory cytokines and chemokines. Lubiprostone attenuates atherosclerosis by ameliorating LGS-induced inflammation through the restoration of the intestinal barrier. These findings raise the possibility of targeting LGS for the treatment of atherosclerosis.
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Affiliation(s)
- Kentaro Arakawa
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Tomoaki Ishigami
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
- * E-mail:
| | - Michiko Nakai-Sugiyama
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Lin Chen
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Hiroshi Doi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Tabito Kino
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Shintaro Minegishi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Sae Saigoh-Teranaka
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Rie Sasaki-Nakashima
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
| | - Kiyoshi Hibi
- Division of Cardiology, Yokohama City University Medical Center, Kanagawa, Japan
| | - Kazuo Kimura
- Division of Cardiology, Yokohama City University Medical Center, Kanagawa, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University, School of Medicine, Kanagawa, Japan
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13
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Jentsch TJ, Pusch M. CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease. Physiol Rev 2018; 98:1493-1590. [DOI: 10.1152/physrev.00047.2017] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl−channels, whereas ClC-3 through ClC-7 are 2Cl−/H+-exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl−channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.
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Affiliation(s)
- Thomas J. Jentsch
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy
| | - Michael Pusch
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany; and Istituto di Biofisica, Consiglio Nazionale delle Ricerche, Genova, Italy
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14
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Sinagra E, Morreale GC, Mohammadian G, Fusco G, Guarnotta V, Tomasello G, Cappello F, Rossi F, Amvrosiadis G, Raimondo D. New therapeutic perspectives in irritable bowel syndrome: Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond. World J Gastroenterol 2017; 23:6593-6627. [PMID: 29085207 PMCID: PMC5643283 DOI: 10.3748/wjg.v23.i36.6593] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/15/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic, recurring, and remitting functional disorder of the gastrointestinal tract characterized by abdominal pain, distention, and changes in bowel habits. Although there are several drugs for IBS, effective and approved treatments for one or more of the symptoms for various IBS subtypes are needed. Improved understanding of pathophysiological mechanisms such as the role of impaired bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and the secretory properties of the gut has led to advancements in the treatment of IBS. With regards to therapies for restoring intestinal permeability, multiple studies with prebiotics and probiotics are ongoing, even if to date their efficacy has been limited. In parallel, much progress has been made in targeting low-grade inflammation, especially through the introduction of drugs such as mesalazine and rifaximin, even if a better knowledge of the mechanisms underlying the low-grade inflammation in IBS may allow the design of clinical trials that test the efficacy and safety of such drugs. This literature review aims to summarize the findings related to new and investigational therapeutic agents for IBS, most recently developed in preclinical as well as Phase 1 and Phase 2 clinical studies.
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Affiliation(s)
- Emanuele Sinagra
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | | | - Ghazaleh Mohammadian
- Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Huddinge, 17176 Stockholm, Sweden
| | - Giorgio Fusco
- Unit of Internal Medicine, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Valentina Guarnotta
- Section of Cardio-Respiratory and Endocrine-Metabolic Diseases, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo 90127, Italy
| | - Giovanni Tomasello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesco Cappello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesca Rossi
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
| | - Georgios Amvrosiadis
- Unit of Gastroenterology, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Dario Raimondo
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
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15
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Gonzalez AA, Salinas-Parra N, Leach D, Navar LG, Prieto MC. PGE 2 upregulates renin through E-prostanoid receptor 1 via PKC/cAMP/CREB pathway in M-1 cells. Am J Physiol Renal Physiol 2017; 313:F1038-F1049. [PMID: 28701311 DOI: 10.1152/ajprenal.00194.2017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/23/2017] [Accepted: 07/10/2017] [Indexed: 12/12/2022] Open
Abstract
During the early phase of ANG II-dependent hypertension, tubular PGE2 is increased. Renin synthesis and secretion in the collecting duct (CD) are upregulated by ANG II, contributing to further intratubular ANG II formation. However, what happens first and whether the triggering mechanism is independent of tubular ANG II remain unknown. PGE2 stimulates renin synthesis in juxtaglomerular cells via E-prostanoid (EP) receptors through the cAMP/cAMP-responsive element-binding (CREB) pathway. EP receptors are also expressed in the CD. Here, we tested the hypothesis that renin is upregulated by PGE2 in CD cells. The M-1 CD cell line expressed EP1, EP3, and EP4 but not EP2. Dose-response experiments, in the presence of ANG II type 1 receptor blockade with candesartan, demonstrated that 10-6 M PGE2 maximally increases renin mRNA (approximately 4-fold) and prorenin/renin protein levels (approximately 2-fold). This response was prevented by micromolar doses of SC-19220 (EP1 antagonist), attenuated by the EP4 antagonist, L-161982, and exacerbated by the highly selective EP3 antagonist, L-798106 (~10-fold increase). To evaluate further the signaling pathway involved, we used the PKC inhibitor calphostin C and transfections with PKCα dominant negative. Both strategies blunted the PGE2-induced increases in cAMP levels, CREB phosphorylation, and augmentation of renin. Knockdown of the EP1 receptor and CREB also prevented renin upregulation. These results indicate that PGE2 increases CD renin expression through the EP1 receptor via the PKC/cAMP/CREB pathway. Therefore, we conclude that during the early stages of ANG II-dependent hypertension, there is augmentation of PGE2 that stimulates renin in the CD, resulting in increased tubular ANG II formation and further stimulation of renin.
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Affiliation(s)
- Alexis A Gonzalez
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile;
| | - Nicolas Salinas-Parra
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Dan Leach
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and
| | - L Gabriel Navar
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.,Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana
| | - Minolfa C Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.,Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana
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16
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Cuppoletti J, Tewari KP, Chakrabarti J, Malinowska DH. Identification of the fatty acid activation site on human ClC-2. Am J Physiol Cell Physiol 2017; 312:C707-C723. [PMID: 28424169 DOI: 10.1152/ajpcell.00267.2016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 04/11/2017] [Accepted: 04/11/2017] [Indexed: 01/26/2023]
Abstract
Fatty acids (including lubiprostone and cobiprostone) are human ClC-2 (hClC-2) Cl- channel activators. Molecular and cellular mechanisms underlying this activation were examined. Role of a four-amino acid PKA activation site, RGET691, of hClC-2 was investigated using wild-type (WT) and mutant (AGET, RGEA, and AGAA) hClC-2 expressed in 293EBNA cells as well as involvement of PKA, intracellular cAMP concentration ([cAMP]i), EP2, or EP4 receptor agonist activity. All fatty acids [lubiprostone, cobiprostone, eicosatetraynoic acid (ETYA), oleic acid, and elaidic acid] caused significant rightward shifts in concentration-dependent Cl- current activation (increasing EC50s) with mutant compared with WT hClC-2 channels, without changing time and voltage dependence, current-voltage rectification, or methadone inhibition of the channel. As with lubiprostone, cobiprostone activation of hClC-2 occurred with PKA inhibitor (myristoylated protein kinase inhibitor) present or when using double PKA activation site (RRAA655/RGEA691) mutant. Cobiprostone did not activate human CFTR. Fatty acids did not increase [cAMP]i in hClC-2/293EBNA or T84 cells. Using T84 CFTR knockdown cells, cobiprostone increased hClC-2 Cl- currents without increasing [cAMP]i, while PGE2 and forskolin-IBMX increased both. Fatty acids were not agonists of EP2 or EP4 receptors. L-161,982, a supposed EP4-selective inhibitor, had no effect on lubiprostone-activated hClC-2 Cl- currents but significantly decreased T84 cell barrier function measured by transepithelial resistance and fluorescent dextran transepithelial movement. The present findings show that RGET691 of hClC-2 (possible binding site) plays an important functional role in fatty acid activation of hClC-2. PKA, [cAMP]i, and EP2 or EP4 receptors are not involved. These studies provide the molecular basis for fatty acid regulation of hClC-2.
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Affiliation(s)
- John Cuppoletti
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio
| | - Kirti P Tewari
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio
| | - Jayati Chakrabarti
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio
| | - Danuta H Malinowska
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio
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17
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Kato T, Honda Y, Kurita Y, Iwasaki A, Sato T, Kessoku T, Uchiyama S, Ogawa Y, Ohkubo H, Higurashi T, Yamanaka T, Usuda H, Wada K, Nakajima A. Lubiprostone improves intestinal permeability in humans, a novel therapy for the leaky gut: A prospective randomized pilot study in healthy volunteers. PLoS One 2017; 12:e0175626. [PMID: 28410406 PMCID: PMC5391961 DOI: 10.1371/journal.pone.0175626] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 03/24/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS The barrier function of the small intestinal mucosa prevents the introduction of undesired pathogens into the body. Breakdown of this barrier function increases intestinal permeability. This has been proposed to induce not only gastrointestinal diseases, including inflammatory bowel disease and irritable bowel syndrome, but also various other diseases, including allergies, diabetes mellitus, liver diseases, and collagen diseases, which are associated with this so called "leaky gut syndrome." As such, a method to prevent leaky gut syndrome would have substantial clinical value. However, no drugs have been demonstrated to improve disturbed intestinal permeability in humans to date. Therefore, we investigated whether a drug used to treat chronic constipation, lubiprostone, was effective for this purpose. METHODS Healthy male volunteers were treated with lubiprostone (24 μg/day) for 28 days. Intestinal permeability was evaluated by measuring the lactulose-mannitol ratio (LMR) after administration of diclofenac and compared with an untreated group. The examination was conducted three times in total, i.e., at baseline before diclofenac administration and after 14 and 28 days of lubiprostone treatment. Blood endotoxin activity was also evaluated at the same time points. RESULTS The final analysis was conducted on 28 subjects (14 in the lubiprostone group and 14 in the untreated group). The LMR after 28 days of treatment was significantly lower in the lubiprostone group than that in the untreated group (0.017 vs. 0.028, respectively; 95% confidence interval, -0.022--0.0001; p = 0.049). Blood endotoxin activity exhibited almost no change over time in the lubiprostone and untreated groups and displayed no significant differences at any time point of examination. CONCLUSIONS This study is the first to report an improvement in leaky gut using an available drug in humans. The result suggests that lubiprostone may prevent and ameliorate "leaky gut syndrome". However, a pivotal trial is needed to confirm our finding.
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Affiliation(s)
- Takayuki Kato
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Yusuke Kurita
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Akito Iwasaki
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Takamitsu Sato
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Shiori Uchiyama
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Yuji Ogawa
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Hidenori Ohkubo
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Takuma Higurashi
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokoahama, Kanagawa, Japan
| | - Haruki Usuda
- Department of Pharmacology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Koichiro Wada
- Department of Pharmacology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
- * E-mail:
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18
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Abstract
Chronic constipation is a common, persistent condition affecting many patients worldwide, presenting significant economic burden and resulting in substantial healthcare utilization. In addition to infrequent bowel movements, the definition of constipation includes excessive straining, a sense of incomplete evacuation, failed or lengthy attempts to defecate, use of digital manoeuvres for evacuation of stool, abdominal bloating, and hard consistency of stools. After excluding secondary causes of constipation, chronic idiopathic or primary constipation can be classified as functional defecation disorder, slow-transit constipation (STC), and constipation-predominant irritable bowel syndrome (IBS-C). These classifications are not mutually exclusive and significant overlap exists. Initial therapeutic approach to primary constipation, regardless of aetiology, consists of diet and lifestyle changes such as encouraging adequate fluid and fibre intake, regular exercise, and dietary modification. Laxatives are the mainstay of pharmacologic treatment for potential long-term therapy in patients who do not respond to lifestyle or dietary modification. After a failed empiric trial of laxatives, diagnostic testing is necessary to understand underlying anorectal and/or colonic pathophysiology. No single test provides a comprehensive assessment for primary constipation; therefore, multiple tests are used to provide complementary information to one another. Dyssynergic defecation, a functional defecation disorder, is an acquired behavioural disorder of defecation present in two-thirds of adult patients, where an inability to coordinate the abdominal, recto-anal, and pelvic floor muscles during attempted defecation exists. Biofeedback therapy is the mainstay treatment for dyssynergic defecation aimed at improving coordination of abdominal and anorectal muscles. A large percentage of patients with dyssynergic defecation also exhibit rectal hyposensitivity and may benefit from the addition of sensory retraining. Our understanding of the pathophysiology of STC is evolving. The advent of high-resolution colonic manometry allows for the improved identification of colonic motor patterns and may provide further insight into pathophysiological mechanisms. In a minority of cases of STC, identification of colonic neuropathy suggests a medically refractory condition, warranting consideration of colectomy. The pathophysiology of IBS-C is poorly understood with multiple etiological factors implicated. Pharmacological advances in the treatment of primary constipation have added therapeutic options to the armamentarium of this disorder. Drug development in the secretagogue, serotonergic prokinetic, and ileal bile acid transporter inhibition pathways has yielded current and future medical treatment options for primary chronic constipation.
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Affiliation(s)
- Amol Sharma
- Division of Gastroenterology and Hepatology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
| | - Satish Rao
- Division of Gastroenterology and Hepatology, Medical College of Georgia, Augusta University, Augusta, GA, USA
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19
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Uekawa K, Koizumi K, Hwang J, Brunier N, Hattori Y, Zhou P, Park L. Obligatory Role of EP1 Receptors in the Increase in Cerebral Blood Flow Produced by Hypercapnia in the Mice. PLoS One 2016; 11:e0163329. [PMID: 27657726 PMCID: PMC5033465 DOI: 10.1371/journal.pone.0163329] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/07/2016] [Indexed: 12/11/2022] Open
Abstract
Hypercapnia induces potent vasodilation in the cerebral circulation. Although it has long been known that prostanoids participate in the cerebrovascular effects of hypercapnia, the role of prostaglandin E2 (PGE2) and PGE2 receptors have not been fully investigated. In this study, we sought to determine whether cyclooxygenase-1 (COX-1)-derived PGE2 and EP1 receptors are involved in the cerebrovascular response induced by hypercapnia. Cerebral blood flow (CBF) was recorded by laser-Doppler flowmetry in the somatosenasory cortex of anesthetized male EP1-/- mice and wild type (WT) littermates. In WT mice, neocortical application of the EP1 receptor antagonist SC-51089 attenuated the increase in CBF elicited by systemic hypercapnia (pCO2 = 50-60 mmHg). SC-51089 also attenuated the increase in CBF produced by neocortical treatment of arachidonic acid or PGE2. These CBF responses were also attenuated in EP1-/- mice. In WT mice, the COX-1 inhibitor SC-560, but not the COX-2 inhibitor NS-398, attenuated the hypercapnic CBF increase. Neocortical application of exogenous PGE2 restored the attenuation in resting CBF and the hypercapnic response induced by SC-560. In contrast, exogenous PGE2 failed to rescue the attenuation both in WT mice induced by SC-51089 and EP1-/- mice, attesting to the obligatory role of EP1 receptors in the response. These findings indicate that the hypercapnic vasodilatation depends on COX-1-derived PGE2 acting on EP1 receptors and highlight the critical role that COX-1-derived PGE2 and EP1 receptors play in the hypercapnic regulation of the cerebral circulation.
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Affiliation(s)
- Ken Uekawa
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America
| | - Kenzo Koizumi
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America
| | - Jason Hwang
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America
| | - Nathalie Brunier
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America
| | - Yorito Hattori
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America
| | - Ping Zhou
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America
| | - Laibaik Park
- Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, 10065, United States of America
- * E-mail:
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20
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Lubiprostone Accelerates Intestinal Transit and Alleviates Small Intestinal Bacterial Overgrowth in Patients With Chronic Constipation. Am J Med Sci 2016; 352:231-8. [DOI: 10.1016/j.amjms.2016.05.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 03/17/2016] [Accepted: 05/17/2016] [Indexed: 12/12/2022]
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21
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Abstract
Constipation is common in the general population and for those on opioids and/or who are suffering from advanced cancer. Self-management consists of dietary changes, exercise, and laxatives. However, responses to self-management efforts are often inadequate to relieve the subjective and objective experience of constipation. Multiple new anti-constipating medications have recently been tested in randomized trials and the following are available commercially: probiotics, prucalopride, lubiprostone, linaclotide, elobixibat, antidepressants, methylnaltrexone, alvimopan, and naloxegol. This review will discuss the evidence-based benefits of these medications and outline an approach to managing constipation.
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Affiliation(s)
- Mellar Davis
- Cleveland Clinic Lerner School of Medicine Case, Western Reserve University, 9500 Euclid Avenue, T34, Cleveland, OH, 44195, USA.
- Clinical Fellowship Program, Cleveland, OH, USA.
- Palliative Medicine and Supportive Oncology Services, Taussig Cancer Institute, Cleveland, OH, USA.
| | - Pamela Gamier
- Cleveland Clinic Lerner School of Medicine Case, Western Reserve University, 9500 Euclid Avenue, T34, Cleveland, OH, 44195, USA
- Clinical Fellowship Program, Cleveland, OH, USA
- Palliative Medicine and Supportive Oncology Services, Taussig Cancer Institute, Cleveland, OH, USA
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22
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Quigley EMM, Neshatian L. Advancing treatment options for chronic idiopathic constipation. Expert Opin Pharmacother 2015; 17:501-11. [PMID: 26630260 DOI: 10.1517/14656566.2016.1127356] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Chronic constipation is a global problem affecting all ages and associated with considerable morbidity and significant financial burden for society. Though formerly defined on the basis of a single symptom, infrequent defecation; constipation is now viewed as a syndrome encompassing several complaints such as difficulty with defecation, a sense of incomplete evacuation, hard stools, abdominal discomfort and bloating. AREAS COVERED The expanded concept of constipation has inevitably led to a significant change in outcomes in clinical trials, as well as in patient expectations from new therapeutic interventions. The past decades have also witnessed a proliferation in therapeutic targets for new agents. Foremost among these have been novel prokinetics, a new category, prosecretory agents and innovative approaches such as inhibitors of bile salt transport. In contrast, relatively few effective therapies exist for the management of those anorectal and pelvic floor problems that result in difficult defecation. EXPERT OPINION Though constipation is a common and often troublesome disorder, many of those affected can resolve their symptoms with relatively simple measures. For those with more resistant symptoms a number of novel, effective and safe options now exist. Those with defecatory difficulty (anismus, pelvic floor dysfunction) continue to represent a significant management challenge.
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Affiliation(s)
- Eamonn M M Quigley
- a Lynda K. and David M. Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology , Houston Methodist Hospital, Weill Cornell Medical College , Houston , TX , USA
| | - Leila Neshatian
- a Lynda K. and David M. Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology , Houston Methodist Hospital, Weill Cornell Medical College , Houston , TX , USA
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23
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Jin Y, Blikslager AT. ClC-2 regulation of intestinal barrier function: Translation of basic science to therapeutic target. Tissue Barriers 2015; 3:e1105906. [PMID: 26716076 DOI: 10.1080/21688370.2015.1105906] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/28/2015] [Accepted: 10/01/2015] [Indexed: 02/06/2023] Open
Abstract
The ClC-2 chloride channel is a member of the voltage-gated chloride channel family. ClC-2 is involved in various physiological processes, including fluid transport and secretion, regulation of cell volume and pH, maintaining the membrane potential of the cell, cell-to-cell communication, and tissue homeostasis. Recently, our laboratory has accumulated evidence indicating a critical role of ClC-2 in the regulation of intestinal barrier function by altering inter-epithelial tight junction composition. This review will detail the role of ClC-2 in intestinal barrier function during intestinal disorders, including experimental ischemia/reperfusion injury and dextran sodium sulfate (DSS)-induced inflammatory bowel disease. Details of pharmacological manipulation of ClC-2 via prostone agonists will also be provided in an effort to show the potential therapeutic relevance of ClC-2 regulation, particularly during intestinal barrier disruption.
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Affiliation(s)
- Younggeon Jin
- Department of Clinical Sciences; College of Veterinary Medicine, North Carolina State University ; Raleigh, NC, USA
| | - Anthony T Blikslager
- Department of Clinical Sciences; College of Veterinary Medicine, North Carolina State University ; Raleigh, NC, USA
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24
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Song J, Yin J, Xu X, Chen J. Prokinetic effects of large-dose lubiprostone on gastrointestinal transit in dogs and its mechanisms. Am J Transl Res 2015; 7:513-521. [PMID: 26045891 PMCID: PMC4448191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 02/24/2015] [Indexed: 06/04/2023]
Abstract
OBJECTIVE To systemically explore effects of large dose of lubiprostone on gastrointestinal (GI) transit and contractions and its safety in dogs. METHODS 12 healthy dogs were studied. 6 dogs were operated to receive duodenal cannula and colon cannula and the other 6 dogs received gastric cannula. Lubiprostone was orally administrated at a dose of 24 µg or 48 µg 1 hr prior to the experiments. Gastric emptying (GE) of solids and small bowel transit were evaluated by collecting the effluents from the duodenal cannula and from the colon cannula. Gastric accommodation was measured by barostat. Gastric and intestinal contractions were by manometry. Colon transit was by X-ray pictures. RESULTS 1) Lubiprostone 48 µg not 24 µg accelerated GE. Atropine could block the effect; 2) Average motility index (MI) of gastric antrum in lubiprostone 48 µg session was significantly higher in both fasting state (P = 0.01) and fed state (P = 0.03). Gastric accommodation was not significantly different; 3) Lubiprostone 48 µg accelerated small bowel and colon transit. Atropine could block the effect on small bowel transit; 4) Lubiprostone 48 µg increased postprandial small bowel MI (P = 0.0008) and colon MI (P = 0.002). 5) No other adverse effects except for diarrhea were observed. CONCLUSION Acute administration of lubiprostone at a dose of 48 µg accelerates GI motility and enhances GI contractions in the postprandial state. The findings suggest that lubiprostone may have an indirect prokinetic effects on the GI tract and vagal activity may be involved. Lubiprostone may be safely used.
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Affiliation(s)
- Jun Song
- Division of Gastroenterology, University of Texas Medical BranchGalveston, Texas
- Department of Gastroenterology, Union Hospital, Huazhong University of Science and TechnologyWuhan, Hubei, China
| | - Jieyun Yin
- Division of Gastroenterology, University of Texas Medical BranchGalveston, Texas
| | - Xiaohong Xu
- Ningbo Pace Translational Medical Research CenterBeilun, Ningbo, China
| | - Jiande Chen
- Division of Gastroenterology, University of Texas Medical BranchGalveston, Texas
- Ningbo Pace Translational Medical Research CenterBeilun, Ningbo, China
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25
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Kang SB, Marchelletta RR, Penrose H, Docherty MJ, McCole DF. A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa. Pharmacol Res Perspect 2015; 3:e00128. [PMID: 26038704 PMCID: PMC4448989 DOI: 10.1002/prp2.128] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 01/19/2015] [Indexed: 12/17/2022] Open
Abstract
Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.
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Affiliation(s)
- Sang Bum Kang
- Division of Gastroenterology, Department of Internal Medicine, St. Mary's Hospital, Catholic University of Korea Seoul, Korea ; Division of Gastroenterology, School of Medicine, University of California, San Diego La Jolla, California
| | - Ronald R Marchelletta
- Division of Gastroenterology, School of Medicine, University of California, San Diego La Jolla, California
| | - Harrison Penrose
- Division of Gastroenterology, School of Medicine, University of California, San Diego La Jolla, California
| | - Michael J Docherty
- Division of Gastroenterology, School of Medicine, University of California, San Diego La Jolla, California
| | - Declan F McCole
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside Riverside, California
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26
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Hussain ZH, Everhart K, Lacy BE. Treatment of Chronic Constipation: Prescription Medications and Surgical Therapies. Gastroenterol Hepatol (N Y) 2015; 11:104-114. [PMID: 27099579 PMCID: PMC4836568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Constipation is a highly prevalent disorder that affects people regardless of age, race, gender, or socioeconomic status. For many patients, constipation is a chronic condition that reduces quality of life. Chronic constipation also imposes a significant economic burden on the health care system. The treatment of constipation remains problematic for both patients and providers for a variety of reasons, including a lack of specificity of symptoms, an inconsistent relationship between underlying pathophysiology and symptom generation, and different and unpredictable patient responses to medications. A large number of over-the-counter agents are used to treat symptoms of constipation, although many of these agents are not effective, and data to support their use are limited and generally of poor quality. Patients referred for consultation typically have failed therapy with over-the-counter agents and require prescription medications or possibly even surgical therapy. This article discusses medical treatments and surgical options for chronic idiopathic constipation.
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Affiliation(s)
- Zilla H Hussain
- Dr Hussain is a gastroenterology fellow, Ms Everhart is a medical student, and Dr Lacy is a professor of medicine and chief of the Section of Gastroenterology and Hepatology at the Geisel School of Medicine at Dartmouth and the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire
| | - Kelly Everhart
- Dr Hussain is a gastroenterology fellow, Ms Everhart is a medical student, and Dr Lacy is a professor of medicine and chief of the Section of Gastroenterology and Hepatology at the Geisel School of Medicine at Dartmouth and the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire
| | - Brian E Lacy
- Dr Hussain is a gastroenterology fellow, Ms Everhart is a medical student, and Dr Lacy is a professor of medicine and chief of the Section of Gastroenterology and Hepatology at the Geisel School of Medicine at Dartmouth and the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire
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Jiao HY, Kim DH, Ki JS, Ryu KH, Choi S, Jun JY. Effects of lubiprostone on pacemaker activity of interstitial cells of cajal from the mouse colon. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 18:341-6. [PMID: 25177167 PMCID: PMC4146637 DOI: 10.4196/kjpp.2014.18.4.341] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 07/09/2014] [Accepted: 07/09/2014] [Indexed: 12/13/2022]
Abstract
Lubiprostone is a chloride (Cl-) channel activator derived from prostaglandin E1 and used for managing constipation. In addition, lubiprostone affects the activity of gastrointestinal smooth muscles. Interstitial cells of Cajal (ICCs) are pacemaker cells that generate slow-wave activity in smooth muscles. We studied the effects of lubiprostone on the pacemaker potentials of colonic ICCs. We used the whole-cell patch-clamp technique to determine the pacemaker activity in cultured colonic ICCs obtained from mice. Lubiprostone hyperpolarized the membrane and inhibited the generation of pacemaker potentials. Prostanoid EP1, EP2, EP3, and EP4 antagonists (SC-19220, PF-04418948, 6-methoxypyridine-2-boronc acid N-phenyldiethanolamine ester, and GW627368, respectively) did not block the response to lubiprostone. L-NG-nitroarginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase) and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, an inhibitor of guanylate cyclase) did not block the response to lubiprostone. In addition, tetraethylammonium (TEA, a voltage-dependent potassium [K+] channel blocker) and apamin (a calcium [Ca2+]-dependent K+ channel blocker) did not block the response to lubiprostone. However, glibenclamide (an ATP-sensitive K+ channel blocker) blocked the response to lubiprostone. Similar to lubiprostone, pinacidil (an opener of ATP-sensitive K+ channel) hyperpolarized the membrane and inhibited the generation of pacemaker potentials, and these effects were inhibited by glibenclamide. These results suggest that lubiprostone can modulate the pacemaker potentials of colonic ICCs via activation of ATP-sensitive K+ channel through a prostanoid EP receptor-independent mechanism.
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Affiliation(s)
- Han-Yi Jiao
- Department of Physiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
| | - Dong Hyun Kim
- Department of Radiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
| | - Jung Suk Ki
- Department of Physiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
| | - Kwon Ho Ryu
- Department of Physiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
| | - Seok Choi
- Department of Physiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
| | - Jae Yeoul Jun
- Department of Physiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
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Eswaran S, Guentner A, Chey WD. Emerging Pharmacologic Therapies for Constipation-predominant Irritable Bowel Syndrome and Chronic Constipation. J Neurogastroenterol Motil 2014; 20:141-51. [PMID: 24840367 PMCID: PMC4015201 DOI: 10.5056/jnm.2014.20.2.141] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/07/2013] [Accepted: 11/20/2013] [Indexed: 12/15/2022] Open
Abstract
Irritable bowel syndrome with constipation and chronic functional constipation are common digestive disorders that negatively impact quality of life and account for billions of dollars in health care costs. Related to the heterogeneity of pathogenesis that underlie these disorders and the failure of symptoms to reliably predict underlying pathophysiology, traditional therapies provide relief to only a subset of affected individuals. The evidence surrounding new and emerging pharmacologic treatments, which include both luminally and systemically acting drugs, is discussed here. These include agents such as lubiprostone, bile acid modulations, guanylate cyclase-C receptor agonists, serotonin receptor modulators and herbal therapies.
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Affiliation(s)
- Shanti Eswaran
- University of Michigan Health System, Ann Arbor, MI, USA
| | | | - William D Chey
- University of Michigan Health System, Ann Arbor, MI, USA
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29
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Hayashi S, Kurata N, Yamaguchi A, Amagase K, Takeuchi K. Lubiprostone prevents nonsteroidal anti-inflammatory drug-induced small intestinal damage by suppressing the expression of inflammatory mediators via EP4 receptors. J Pharmacol Exp Ther 2014; 349:470-9. [PMID: 24713141 DOI: 10.1124/jpet.114.213991] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of the chloride channel protein 2/cystic fibrosis transmembrane regulator (ClC-2/CFTR) chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male Sprague-Dawley rats were administered indomethacin (10 mg/kg p.o.) and killed 24 hours later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1 mg/kg) was administered orally twice 30 minutes before and 9 h after the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor α (TNFα) mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the coadministration of AE3-208 [4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid], a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggest that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/TNFα expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is not likely to have contributed to the protective effects of lubiprostone.
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MESH Headings
- Alprostadil/administration & dosage
- Alprostadil/analogs & derivatives
- Alprostadil/therapeutic use
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/toxicity
- Anti-Ulcer Agents/administration & dosage
- Anti-Ulcer Agents/therapeutic use
- Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics
- Gastrointestinal Hemorrhage/chemically induced
- Gastrointestinal Hemorrhage/prevention & control
- Gastrointestinal Motility/drug effects
- Intestinal Mucosa/drug effects
- Intestinal Mucosa/immunology
- Intestinal Mucosa/metabolism
- Intestinal Mucosa/pathology
- Intestine, Small/drug effects
- Intestine, Small/immunology
- Intestine, Small/metabolism
- Intestine, Small/pathology
- Lubiprostone
- Male
- Naphthalenes/pharmacology
- Nitric Oxide Synthase Type II/biosynthesis
- Phenylbutyrates/pharmacology
- Rats
- Rats, Sprague-Dawley
- Receptors, Prostaglandin E, EP4 Subtype/genetics
- Receptors, Prostaglandin E, EP4 Subtype/metabolism
- Tumor Necrosis Factor-alpha/biosynthesis
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Affiliation(s)
- Shusaku Hayashi
- Department of Pharmacology and Experimental Therapeutics, Division of Pathological Sciences, Kyoto Pharmaceutical University, Misasagi, Yamashina (S.H., N.K., A.Y., K.A., K.T.); and General Incorporated Association, Kyoto Research Center for Gastrointestinal Diseases, Karasuma-Oike (K.T.), Kyoto, Japan
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Lacy BE, Hussain ZH, Mearin F. Treatment for constipation: new and old pharmacological strategies. Neurogastroenterol Motil 2014; 26:749-63. [PMID: 24860968 DOI: 10.1111/nmo.12335] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 03/05/2014] [Indexed: 12/19/2022]
Abstract
BACKGROUND Constipation is a very common entity. Despite the high prevalence, treatment of constipation remains problematic. PURPOSE Review the current literature on new and existing constipation treatment modalities.
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Affiliation(s)
- B E Lacy
- Division of Gastroenterology & Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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31
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Raschi E, De Ponti F. Lubiprostone: pharmacokinetic, pharmacodynamic, safety and regulatory aspects in the treatment of constipation-predominant irritable bowel syndrome. Expert Opin Drug Metab Toxicol 2014; 10:293-305. [PMID: 24387275 DOI: 10.1517/17425255.2013.876410] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Lubiprostone acts locally (apical membrane of human intestinal epithelial cells) as a highly selective type-2 chloride channel activator. It was approved in the USA for chronic idiopathic constipation (January 2006) and in women aged ≥ 18 years suffering from irritable bowel syndrome with constipation (IBS-C) (April 2008). So far, the only other pro-secretory medication approved in IBS-C and currently available in USA and Europe (since August and November 2012, respectively) is linaclotide. AREAS COVERED This review outlines the regulatory history, pharmacokinetic, pharmacodynamic and safety data in the treatment of IBS-C with a European perspective. It is based on publicly available data, namely, published literature, drug labels and the FDA's spontaneous reporting system. EXPERT OPINION Although interesting pharmacodynamic data suggest that lubiprostone may have additional mechanisms of action, its beneficial effects in IBS-C must be confirmed in the actual clinical scenario taking into account the new version of European Medicines Agency's guideline. This is especially important with regard to duration of studies (recommended to be at least 6 months) to adequately assess long-term sustained efficacy, withdrawal, rebound and safety. Further research is warranted in uncertain areas (i.e., males, pediatric and elderly patients). On the basis of current data, it is still too early to draw definite conclusions on the overall risk-benefit balance for IBS-C.
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Affiliation(s)
- Emanuel Raschi
- University of Bologna, Department of Medical and Surgical Sciences, Pharmacology Unit, Alma Mater Studiorum , Via Irnerio, 48, I-40126 Bologna BO , Italy
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Pustovit RV, Callaghan B, Kosari S, Rivera LR, Thomas H, Brock JA, Furness JB. The mechanism of enhanced defecation caused by the ghrelin receptor agonist, ulimorelin. Neurogastroenterol Motil 2014; 26:264-71. [PMID: 24304447 DOI: 10.1111/nmo.12259] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Accepted: 10/11/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Discovery of adequate pharmacological treatments for constipation has proven elusive. Increased numbers of bowel movements were reported as a side-effect of ulimorelin treatment of gastroparesis, but there has been no investigation of the site of action. METHODS Anesthetized rats were used to investigate sites and mechanisms of action of ulimorelin. KEY RESULTS Intravenous ulimorelin (1-5 mg/kg) caused a substantial and prolonged (~1 h) increase in colorectal propulsive activity and expulsion of colonic contents. This was prevented by cutting the nerves emerging from the lumbosacral cord, by the nicotinic receptor antagonist hexamethonium and by antagonists of the ghrelin receptor. The effect of intravenous ulimorelin was mimicked by direct application of ulimorelin (5 μg) to the lumbosacral spinal cord. CONCLUSIONS & INFERENCES Ulimorelin is a potent prokinetic that causes propulsive contractions of the colorectum by activating ghrelin receptors of the lumbosacral defecation centers. Its effects are long-lasting, in contrast with other colokinetics that target ghrelin receptors.
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Affiliation(s)
- R V Pustovit
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, VIC, Australia
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33
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Stauber T, Weinert S, Jentsch TJ. Cell biology and physiology of CLC chloride channels and transporters. Compr Physiol 2013; 2:1701-44. [PMID: 23723021 DOI: 10.1002/cphy.c110038] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Proteins of the CLC gene family assemble to homo- or sometimes heterodimers and either function as Cl(-) channels or as Cl(-)/H(+)-exchangers. CLC proteins are present in all phyla. Detailed structural information is available from crystal structures of bacterial and algal CLCs. Mammals express nine CLC genes, four of which encode Cl(-) channels and five 2Cl(-)/H(+)-exchangers. Two accessory β-subunits are known: (1) barttin and (2) Ostm1. ClC-Ka and ClC-Kb Cl(-) channels need barttin, whereas Ostm1 is required for the function of the lysosomal ClC-7 2Cl(-)/H(+)-exchanger. ClC-1, -2, -Ka and -Kb Cl(-) channels reside in the plasma membrane and function in the control of electrical excitability of muscles or neurons, in extra- and intracellular ion homeostasis, and in transepithelial transport. The mainly endosomal/lysosomal Cl(-)/H(+)-exchangers ClC-3 to ClC-7 may facilitate vesicular acidification by shunting currents of proton pumps and increase vesicular Cl(-) concentration. ClC-3 is also present on synaptic vesicles, whereas ClC-4 and -5 can reach the plasma membrane to some extent. ClC-7/Ostm1 is coinserted with the vesicular H(+)-ATPase into the acid-secreting ruffled border membrane of osteoclasts. Mice or humans lacking ClC-7 or Ostm1 display osteopetrosis and lysosomal storage disease. Disruption of the endosomal ClC-5 Cl(-)/H(+)-exchanger leads to proteinuria and Dent's disease. Mouse models in which ClC-5 or ClC-7 is converted to uncoupled Cl(-) conductors suggest an important role of vesicular Cl(-) accumulation in these pathologies. The important functions of CLC Cl(-) channels were also revealed by human diseases and mouse models, with phenotypes including myotonia, renal loss of salt and water, deafness, blindness, leukodystrophy, and male infertility.
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Affiliation(s)
- Tobias Stauber
- Leibniz-Institut für Molekulare Pharmakologie FMP and Max-Delbrück-Centrum für Molekulare Medizin MDC, Berlin, Germany
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Abstract
INTRODUCTION Chronic constipation (CC) is a common problem worldwide and, for some sufferers, a cause of considerable morbidity. Recent definitions of CC have moved from the former emphasis on stool frequency alone to a broader concept that strives to encompass the various symptoms that may bother afflicted individuals. Accordingly, new therapies attempt to not only increase frequency of defecation but also to address such symptoms as satisfaction with bowel action, straining, bloating, and distension. AREAS COVERED To provide context the relative merits and problems related to conventional laxative-based approaches to constipation are first reviewed and then more recent novel pharmacological approaches to the management of constipation assessed. The focus is on two classes of compounds, selective prokinetics and prosecretory agents, and studies on their efficacy and safety in chronic idiopathic constipation were retrieved and evaluated. EXPERT OPINION While undoubtedly effective, high-quality evidence to support laxatives, the traditional remedies for constipation, is remarkably scarce due, in large part, to the absence, until very recently, of high-quality randomized controlled clinical trials. The selective prokinetic agent prucalopride and the prosecretory agents lubiprostone and linaclotide have shown efficacy and been associated with a good safety record in large well-conducted clinical studies. Other novel approaches, such as the inhibition of ileal bile salt absorption, offer particular promise.
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35
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Jun JY. Role of lubiprostone on gastrointestinal motility. J Neurogastroenterol Motil 2013; 19:277-8. [PMID: 23875092 PMCID: PMC3714403 DOI: 10.5056/jnm.2013.19.3.277] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Revised: 06/04/2013] [Accepted: 06/06/2013] [Indexed: 01/10/2023] Open
Affiliation(s)
- Jae Yeoul Jun
- Department of Physiology, Chosun University School of Medicine, Gwangju, Korea
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36
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Chan WW, Mashimo H. Lubiprostone Increases Small Intestinal Smooth Muscle Contractions Through a Prostaglandin E Receptor 1 (EP1)-mediated Pathway. J Neurogastroenterol Motil 2013; 19:312-8. [PMID: 23875097 PMCID: PMC3714408 DOI: 10.5056/jnm.2013.19.3.312] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2013] [Revised: 04/18/2013] [Accepted: 04/19/2013] [Indexed: 12/28/2022] Open
Abstract
Background/Aims Lubiprostone, a chloride channel type 2 (ClC-2) activator, was thought to treat constipation by enhancing intestinal secretion. It has been associated with increased intestinal transit and delayed gastric emptying. Structurally similar to prostones with up to 54% prostaglandin E2 activity on prostaglandin E receptor 1 (EP1), lubiprostone may also exert EP1-mediated procontractile effect on intestinal smooth muscles. We investigated lubiprostone's effects on intestinal smooth muscle contractions and pyloric sphincter tone. Methods Isolated murine small intestinal (longitudinal and circular) and pyloric tissues were mounted in organ baths with modified Krebs solution for isometric recording. Basal muscle tension and response to electrical field stimulation (EFS; 2 ms pulses/10 V/6 Hz/30 sec train) were measured with lubiprostone (10-10-10-5 M) ± EP1 antagonist. Significance was established using Student t test and P < 0.05. Results Lubiprostone had no effect on the basal tension or EFS-induced contractions of longitudinal muscles. With circular muscles, lubiprostone caused a dose-dependent increase in EFS-induced contractions (2.11 ± 0.88 to 4.43 ± 1.38 N/g, P = 0.020) that was inhibited by pretreatment with EP1 antagonist (1.69 ± 0.70 vs. 4.43 ± 1.38 N/g, P = 0.030). Lubiprostone had no effect on circular muscle basal tension, but it induced a dose-dependent increase in pyloric basal tone (1.07 ± 0.01 to 1.97 ± 0.86 fold increase, P < 0.05) that was inhibited by EP1 antagonist. Conclusions In mice, lubiprostone caused a dose-dependent and EP1-mediated increase in contractility of circular but not longitudinal small intestinal smooth muscles, and in basal tone of the pylorus. These findings suggest another mechanism for lubiprostone's observed clinical effects on gastrointestinal motility.
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Affiliation(s)
- Walter W Chan
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA. ; Harvard Medical School, Boston, MA, USA
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Konya V, Marsche G, Schuligoi R, Heinemann A. E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther 2013; 138:485-502. [PMID: 23523686 PMCID: PMC3661976 DOI: 10.1016/j.pharmthera.2013.03.006] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 03/07/2013] [Indexed: 01/06/2023]
Abstract
The large variety of biological functions governed by prostaglandin (PG) E2 is mediated by signaling through four distinct E-type prostanoid (EP) receptors. The availability of mouse strains with genetic ablation of each EP receptor subtype and the development of selective EP agonists and antagonists have tremendously advanced our understanding of PGE2 as a physiologically and clinically relevant mediator. Moreover, studies using disease models revealed numerous conditions in which distinct EP receptors might be exploited therapeutically. In this context, the EP4 receptor is currently emerging as most versatile and promising among PGE2 receptors. Anti-inflammatory, anti-thrombotic and vasoprotective effects have been proposed for the EP4 receptor, along with its recently described unfavorable tumor-promoting and pro-angiogenic roles. A possible explanation for the diverse biological functions of EP4 might be the multiple signaling pathways switched on upon EP4 activation. The present review attempts to summarize the EP4 receptor-triggered signaling modules and the possible therapeutic applications of EP4-selective agonists and antagonists.
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Key Words
- ampk, amp-activated protein kinase
- camp, cyclic adenylyl monophosphate
- cftr, cystic fibrosis transmembrane conductance regulator
- clc, chloride channel
- cox, cyclooxygenase
- creb, camp-response element-binding protein
- dp, d-type prostanoid receptor
- dss, dextran sodium sulfate
- egfr, epidermal growth factor receptor
- enos, endothelial nitric oxide synthase
- ep, e-type prostanoid receptor
- epac, exchange protein activated by camp
- eprap, ep4 receptor-associated protein
- erk, extracellular signal-regulated kinase
- fem1a, feminization 1 homolog a
- fp, f-type prostanoid receptor
- grk, g protein-coupled receptor kinase
- 5-hete, 5-hydroxyeicosatetraenoic acid
- icer, inducible camp early repressor
- icam-1, intercellular adhesion molecule-1
- ig, immunoglobulin
- il, interleukin
- ifn, interferon
- ip, i-type prostanoid receptor
- lps, lipopolysaccharide
- map, mitogen-activated protein kinase
- mcp, monocyte chemoattractant protein
- mek, map kinase kinase
- nf-κb, nuclear factor kappa-light-chain-enhancer of activated b cells
- nsaid, non-steroidal anti-inflammatory drug
- pg, prostaglandin
- pi3k, phosphatidyl insositol 3-kinase
- pk, protein kinase
- tp, t-type prostanoid receptor
- tx, thromboxane receptor
- prostaglandins
- inflammation
- vascular disease
- cancerogenesis
- renal function
- osteoporosis
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Affiliation(s)
| | | | | | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria
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Sherid M, Sifuentes H, Samo S, Deepak P, Sridhar S. Lubiprostone induced ischemic colitis. World J Gastroenterol 2013; 19:299-303. [PMID: 23345954 PMCID: PMC3547564 DOI: 10.3748/wjg.v19.i2.299] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Revised: 10/30/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
Ischemic colitis accounts for 6%-18% of the causes of acute lower gastrointestinal bleeding. It is often multifactorial and more commonly encountered in the elderly. Several medications have been implicated in the development of colonic ischemia. We report a case of a 54-year old woman who presented with a two-hour history of nausea, vomiting, abdominal pain, and bloody stool. The patient had recently used lubiprostone with close temporal relationship between the increase in the dose and her symptoms of rectal bleeding. The radiologic, colonoscopic and histopathologic findings were all consistent with ischemic colitis. Her condition improved without any serious complications after the cessation of lubiprostone. This is the first reported case of ischemic colitis with a clear relationship with lubiprostone (Naranjo score of 10). Clinical vigilance for ischemic colitis is recommended for patients receiving lubiprostone who are presenting with abdominal pain and rectal bleeding.
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BHARUCHA ADILE, PEMBERTON JOHNH, LOCKE GRICHARD. American Gastroenterological Association technical review on constipation. Gastroenterology 2013; 144:218-38. [PMID: 23261065 PMCID: PMC3531555 DOI: 10.1053/j.gastro.2012.10.028] [Citation(s) in RCA: 540] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- ADIL E. BHARUCHA
- Division of Gastroenterology and Hepatology Mayo Clinic and Mayo Medical School Rochester, Minnesota
| | - JOHN H. PEMBERTON
- Division of Colon and Rectal Surgery Mayo Clinic and Mayo Medical School Rochester, Minnesota
| | - G. RICHARD LOCKE
- Division of Gastroenterology and Hepatology Mayo Clinic and Mayo Medical School Rochester, Minnesota
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Zhou J, Alvarez-Elizondo MB, Botvinick E, George SC. Adenosine A(1) and prostaglandin E receptor 3 receptors mediate global airway contraction after local epithelial injury. Am J Respir Cell Mol Biol 2012; 48:299-305. [PMID: 23221044 DOI: 10.1165/rcmb.2012-0174oc] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Epithelial injury and airway hyperresponsiveness are prominent features of asthma. We have previously demonstrated that laser ablation of single epithelial cells immediately induces global airway constriction through Ca(2+)-dependent smooth muscle shortening. The response is mediated by soluble mediators released from wounded single epithelial cells; however, the soluble mediators and signaling mechanisms have not been identified. In this study, we investigated the nature of the epithelial-derived soluble mediators and the associated signaling pathways that lead to the L-type voltage-dependent Ca(2+) channel (VGCC)-mediated Ca(2+) influx. We found that inhibition of adenosine A1 receptors (or removal of adenosine with adenosine deaminase), cyclooxygenase (COX)-2 or prostaglandin E receptor 3 (EP3) receptors, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor (PDGFR) all significantly blocked Ca(2+) oscillations in smooth muscle cells and airway contraction induced by local epithelial injury. Using selective agonists to activate the receptors in the presence and absence of selective receptor antagonists, we found that adenosine activated the signaling pathway A1R→EGFR/PDGFR→COX-2→EP3→VGCCs→calcium-induced calcium release, leading to intracellular Ca(2+) oscillations in airway smooth muscle cells and airway constriction.
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Affiliation(s)
- Jian Zhou
- Department of Biomedical Engineering, 2420 Engineering Hall, University of California, Irvine, CA 92697-2715, USA
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Fairbrother SE, Smith JE, Borman RA, Cox HM. EP4 receptors mediate prostaglandin E2, tumour necrosis factor alpha and interleukin 1beta-induced ion secretion in human and mouse colon mucosa. Eur J Pharmacol 2012; 694:89-97. [DOI: 10.1016/j.ejphar.2012.06.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Revised: 05/29/2012] [Accepted: 06/09/2012] [Indexed: 01/12/2023]
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Lubiprostone targets prostanoid signaling and promotes ion transporter trafficking, mucus exocytosis, and contractility. Dig Dis Sci 2012; 57:2826-45. [PMID: 22923315 PMCID: PMC3482986 DOI: 10.1007/s10620-012-2352-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 07/28/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Lubiprostone is a chloride channel activator in clinical use for the treatment of chronic constipation, but the mechanisms of action of the drug are poorly understood. The aim of this study was to determine whether lubiprostone exerts secretory effects in the intestine by membrane trafficking of ion transporters and associated machinery. METHODS Immunolabeling and quantitative fluorescence intensity were used to examine lubiprostone-induced trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR), sodium/potassium-coupled chloride co-transporter 1 (NKCC1), electrogenic sodium/bicarbonate co-transporter 1 (NBCe1), down-regulated in adenoma (DRA), putative anion transporter 1 (PAT1), sodium/proton exchanger 3 (NHE3), Ca(2+) activated chloride channel 2 (ClC-2) serotonin and its transporter SERT, E prostanoid receptors EP4 and EP1, sodium/potassium ATPase (Na-K-ATPase) and protein kinase A (PKA). The effects of lubiprostone on mucus exocytosis in rat intestine and human rectosigmoid explants were also examined. RESULTS Lubiprostone induced contraction of villi and proximal colonic plicae and membrane trafficking of transporters that was more pronounced in villus/surface cells compared to the crypt. Membrane trafficking was determined by: (1) increased membrane labeling for CFTR, PAT1, NKCC1, and NBCe1 and decreased membrane labeling for NHE3, DRA and ClC-2; (2) increased serotonin, SERT, EP4, EP1 and PKA labeling in enterochromaffin cells; (3) increased SERT, EP4, EP1, PKA and Na-K-ATPase in enterocytes; and (4) increased mucus exocytosis in goblet cells. CONCLUSION These data suggest that lubiprostone can target serotonergic, EP4/PKA and EP1 signaling in surface/villus regions; stimulate membrane trafficking of CFTR/NBCe1/NKCC1 in villus epithelia and PAT1/NBCe1/NKCC1 in colonic surface epithelia; suppress NHE3/DRA trafficking and fluid absorption; and enhance mucus-mobilization and mucosal contractility.
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Akiba Y, Kaunitz JD. May the truth be with you: lubiprostone as EP receptor agonist/ClC-2 internalizing "inhibitor". Dig Dis Sci 2012; 57:2740-2. [PMID: 23001408 DOI: 10.1007/s10620-012-2410-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Norimatsu Y, Moran AR, MacDonald KD. Lubiprostone activates CFTR, but not ClC-2, via the prostaglandin receptor (EP(4)). Biochem Biophys Res Commun 2012; 426:374-9. [PMID: 22960173 DOI: 10.1016/j.bbrc.2012.08.097] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Accepted: 08/21/2012] [Indexed: 11/19/2022]
Abstract
The goal of this study was to determine the mechanism of lubiprostone activation of epithelial chloride transport. Lubiprostone is a bicyclic fatty acid approved for the treatment of constipation [1]. There is uncertainty, however, as to how lubiprostone increases epithelial chloride transport. Direct stimulation of ClC-2 and CFTR chloride channels as well as stimulation of these channels via the EP(4) receptor has been described [2-5]. To better define this mechanism, two-electrode voltage clamp was used to assay Xenopus oocytes expressing ClC-2, with or without co-expression of the EP(4) receptor or β adrenergic receptor (βAR), for changes in conductance elicited by lubiprostone. Oocytes co-expressing CFTR and either βAR or the EP(4) receptor were also studied. In oocytes co-expressing ClC-2 and βAR conductance was stimulated by hyperpolarization and acidic pH (pH = 6), but there was no response to the β adrenergic agonist, isoproterenol. Oocytes expressing ClC-2 only or co-expressing ClC-2 and EP(4) did not respond to the presence of 0.1, 1, or 10 μM lubiprostone in the superperfusate. Oocytes co-expressing CFTR and βAR did not respond to hyperpolarization, acidic pH, or 1 μM lubiprostone. However, conductance was elevated by isoproterenol and inhibited by CFTR(inh)172. Co-expression of CFTR and EP(4) resulted in lubiprostone-stimulated conductance, which was also sensitive to CFTR(inh)172. The EC(50) for lubiprostone mediated CFTR activation was ~10 nM. These results demonstrate no direct action of lubiprostone on either ClC-2 or CFTR channels expressed in oocytes. However, the results confirm that CFTR can be activated by lubiprostone via the EP(4) receptor in oocytes.
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Affiliation(s)
- Yohei Norimatsu
- Department of Physiology - Pharmacology, Oregon Health and Science University, OR 97239, USA
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Chamberlain SM, Rao SSC. Safety evaluation of lubiprostone in the treatment of constipation and irritable bowel syndrome. Expert Opin Drug Saf 2012; 11:841-50. [PMID: 22834474 DOI: 10.1517/14740338.2012.708732] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Lubiprostone is approved in the United States for the treatment of chronic idiopathic constipation and constipation predominant irritable bowel syndrome (IBS-C). Lubiprostone causes secretion of fluid and electrolytes in the small bowel, through the activation of chloride channels, and thereby induces laxation and improvement of bowel functions. It is generally considered to be safe and effective. Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction. AREAS COVERED This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages. EXPERT OPINION Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown.
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Affiliation(s)
- Sherman M Chamberlain
- Section of Gastroenterology and Hepatology, Medical College of Georgia, Georgia Health Sciences University, 1120 15th Street, Augusta, GA 30912, USA
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Vio CP, Quiroz-Munoz M, Cuevas CA, Cespedes C, Ferreri NR. Prostaglandin E2 EP3 receptor regulates cyclooxygenase-2 expression in the kidney. Am J Physiol Renal Physiol 2012; 303:F449-57. [PMID: 22622465 DOI: 10.1152/ajprenal.00634.2011] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Cyclooxygenase-2 (COX-2) is constitutively expressed and highly regulated in the thick ascending limb (TAL). As COX-2 inhibitors (Coxibs) increase COX-2 expression, we tested the hypothesis that a negative feedback mechanism involving PGE(2) EP3 receptors regulates COX-2 expression in the TAL. Sprague-Dawley rats were treated with a Coxib [celecoxib (20 mg·kg(-1)·day(-1)) or rofecoxib (10 mg·kg(-1)·day(-1))], with or without sulprostone (20 μg·kg(-1)·day(-1)). Sulprostone was given using two protocols, namely, previous to Coxib treatment (prevention effect; Sulp7-Coxib5 group) and 5 days after initiation of Coxib treatment (regression effect; Coxib10-Sulp5 group). Immunohistochemical and morphometric analysis revealed that the stained area for COX-2-positive TAL cells (μm(2)/field) increased in Coxib-treated rats (Sham: 412 ± 56.3, Coxib: 794 ± 153.3). The Coxib effect was inhibited when sulprostone was used in either the prevention (285 ± 56.9) or regression (345 ± 51.1) protocols. Western blot analysis revealed a 2.1 ± 0.3-fold increase in COX-2 protein expression in the Coxib-treated group, an effect abolished by sulprostone using either the prevention (1.2 ± 0.3-fold) or regression (0.6 ± 0.4-fold vs. control, P < 0.05) protocols. Similarly, the 6.4 ± 0.6-fold increase in COX-2 mRNA abundance induced by Coxibs (P < 0.05) was inhibited by sulprostone; prevention: 0.9 ± 0.3-fold (P < 0.05) and regression: 0.6 ± 0.1 (P < 0.05). Administration of a selective EP3 receptor antagonist, L-798106, also increased the area for COX-2-stained cells, COX-2 mRNA accumulation, and protein expression in the TAL. Collectively, the data suggest that COX-2 levels are regulated by a novel negative feedback loop mediated by PGE(2) acting on its EP3 receptor in the TAL.
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Affiliation(s)
- Carlos P Vio
- Dept. of Physiology, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Alameda 340, Santiago, Chile.
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Catalán MA, Flores CA, González-Begne M, Zhang Y, Sepúlveda FV, Melvin JE. Severe defects in absorptive ion transport in distal colons of mice that lack ClC-2 channels. Gastroenterology 2012; 142:346-54. [PMID: 22079595 PMCID: PMC3267842 DOI: 10.1053/j.gastro.2011.10.037] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2011] [Revised: 10/25/2011] [Accepted: 10/26/2011] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS The fluid secretion model predicts that intestinal obstruction disorders can be alleviated by promoting epithelial Cl(-) secretion. The adenosine 3',5'-cyclic monophosphate (cAMP)-activated anion channel CFTR mediates Cl(-)-dependent fluid secretion in the intestine. Although the role of the ClC-2 channel has not been determined in the intestine, this voltage-gated Cl(-) channel might compensate for the secretory defects observed in patients with cystic fibrosis and other chronic constipation disorders. We investigated whether mice that lack ClC-2 channels (Clcn2(-/-)) have defects in intestinal ion transport. METHODS Immunolocalization and immunoblot analyses were used to determine the cellular localization and the amount of ClC-2 expressed in mouse early distal colon (EDC) and late distal colon (LDC). Colon sheets from wild-type and Clcn2(-/-) littermates were mounted in Ussing chambers to determine transepithelial bioelectrical parameters and Na(+), K(+), and Cl(-) fluxes. RESULTS Expression of ClC-2 was higher in the basolateral membrane of surface cells in the EDC compared with the LDC, with little expression in crypts. Neither cAMP nor Ca(2+)-induced secretion of Cl(-) was affected in the EDC or LDC of Clcn2(-/-) mice, whereas the amiloride-sensitive short-circuit current was increased approximately 3-fold in Clcn2(-/-) EDC compared with control littermates. Conversely, electroneutral Na(+), K(+), and Cl(-) absorption was dramatically reduced in colons of Clcn2(-/-) mice. CONCLUSIONS Basolateral ClC-2 channels are required for colonic electroneutral absorption of NaCl and KCl. The increase in the amiloride-sensitive short-circuit current in Clcn2(-/-) mice revealed a compensatory mechanism that is activated in the colons of mice that lack the ClC-2 channel.
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Affiliation(s)
- Marcelo A. Catalán
- Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Building 10/Room 5N102, Bethesda, MD 20892 USA
| | | | - Mireya González-Begne
- Center for Oral Biology, University of Rochester Medical Center, Rochester, NY 14642 USA
| | - Yan Zhang
- Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Building 10/Room 5N102, Bethesda, MD 20892 USA
| | | | - James E. Melvin
- Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 10 Center Drive, Building 10/Room 5N102, Bethesda, MD 20892 USA
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Lin YM, Sarna SK, Shi XZ. Prophylactic and therapeutic benefits of COX-2 inhibitor on motility dysfunction in bowel obstruction: roles of PGE₂ and EP receptors. Am J Physiol Gastrointest Liver Physiol 2012; 302:G267-75. [PMID: 22038825 PMCID: PMC3341114 DOI: 10.1152/ajpgi.00326.2011] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We reported previously that mechanical stretch in rat colonic obstruction induces cyclooxygenase (COX)-2 expression in smooth muscle cells. The aims of the present study were to investigate whether in vivo treatment with COX-2 inhibitor has prophylactic and therapeutic effects on motility dysfunction in colon obstruction, and if so what are the underlying mechanisms. Partial colon obstruction was induced with a silicon band in the distal colon of 6-8-wk-old Sprague-Dawley rats; obstruction was maintained for 3 days or 7 days. Daily administration of COX-2 inhibitor NS-398 (5 mg/kg) or vehicle was started before or after the induction of obstruction to study its prophylactic and therapeutic effects, respectively. The smooth muscle contractility was significantly suppressed, and colonic transit rate was slower in colonic obstruction. Prophylactic treatment with NS-398 significantly prevented the impairments of colonic transit and smooth muscle contractility and attenuated fecal collection in the occluded colons. When NS-398 was administered therapeutically 3 days after the initiation of obstruction, the muscle contractility and colonic transit still improved on day 7. Obstruction led to marked increase of COX-2 expression and prostaglandin E(2) (PGE(2)) synthesis. Exogenous PGE(2) decreased colonic smooth muscle contractility. All four PGE(2) E-prostanoid receptor types (EP1 to EP4) were detected in rat colonic muscularis externa. Treatments with EP1 and EP3 antagonists suppressed muscle contractility in control tissue but did not improve contractility in obstruction tissue. On the contrary, the EP2 and EP4 antagonists did not affect control tissue but significantly restored muscle contractility in obstruction. We concluded that our study shows that COX-2 inhibitor has prophylactic and therapeutic benefits for motility dysfunction in bowel obstruction. PGE(2) and its receptors EP2 and EP4 are involved in the motility dysfunction in obstruction, whereas EP1 and EP3 mediate PGE(2) regulation of colonic smooth muscle contractile function in normal state.
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Affiliation(s)
- You-Min Lin
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
| | - Sushil K. Sarna
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
| | - Xuan-Zheng Shi
- Division of Gastroenterology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas
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Pharmacology of the New Treatments for Lower Gastrointestinal Motility Disorders and Irritable Bowel Syndrome. Clin Pharmacol Ther 2011; 91:44-59. [DOI: 10.1038/clpt.2011.261] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Camilleri M. New treatment options for chronic constipation: mechanisms, efficacy and safety. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2011; 25 Suppl B:29B-35B. [PMID: 22114755 PMCID: PMC3206563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Accepted: 06/10/2011] [Indexed: 05/31/2023]
Abstract
The present review has several objectives, the first of which is to review the pharmacology and selectivity of serotonergic agents to contrast the older serotonergic agents (which were withdrawn because of cardiac or vascular adverse effects) with the newer generation serotonin receptor subtype 4 agonists. Second, the chloride ion secretagogues that act through the guanylate cyclase C receptor are appraised and their pharmacology is compared with the approved medication, lubiprostone. Third, the efficacy and safety of the application of bile acid modulation to treat constipation are addressed. The long-term studies of surgically induced excess bile acid delivery to the colon are reviewed to ascertain the safety of this therapeutic approach. Finally, the new drugs for opiate-induced constipation are introduced. Assuming these drugs are approved, practitioners will have a choice; however, patient responsiveness will be based on trial and error. Nevertheless, the spectrum of mechanisms and demonstrated efficacy and safety augur well for satisfactory treatment outcomes.
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