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Santos LGAA, Musther H, Bala N, Deferm N, Patel G, Brouwers J, Turner DB. Gastrointestinal Bile Salt Concentrations in Healthy Adults Under Fasted and Fed Conditions: A Systematic Review and Meta-Analysis for Mechanistic Physiologically-Based Pharmacokinetic (PBPK) Modelling. AAPS J 2025; 27:31. [PMID: 39843813 DOI: 10.1208/s12248-025-01016-x] [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: 10/02/2024] [Accepted: 01/06/2025] [Indexed: 01/24/2025] Open
Abstract
Bile salts are biosurfactants released into the intestinal lumen which play an important role in the solubilisation of fats and certain drugs. Their concentrations vary along the gastrointestinal tract (GIT). This is significant for implementation in physiologically based pharmacokinetic (PBPK) modelling to mechanistically capture drug absorption. The aims of this meta-analysis were to collate all appropriate data on intestinal bile salt concentrations in healthy adults across all GIT segments in fasted and fed states for the purpose of PBPK modelling. Terms relating to bile composition were searched in PubMed and Google Scholar from inception to May 2024. Selected studies included aspirated intestinal fluid collected via gastric tubes or colonoscopy. Results showed high variability across studies and a time-dependency for the fed state. Data were rich for the duodenum, which showed a two-fold increase for the fed state versus the fasted state within multiple studies. Peaks and troughs in bile salt concentrations along the GIT were observed for both fasted and fed states, likely due to segmental water absorption differences. The highest between subject variability was observed for the duodenum in the fasted and fed state and the fed proximal jejunum, distal ileum, and colon. The findings from this meta-analysis can be used for the purpose of PBPK modelling to capture segmental drug solubilisation and absorption in fasted and fed states. However, data are lacking under different fed conditions, especially following low-fat meals, so the impact of different fat content associated with different meals on bile salt concentrations cannot be discerned.
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Affiliation(s)
| | - Helen Musther
- Certara UK Limited, Level 2, Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK
| | - Neeru Bala
- Certara UK Limited, Level 2, Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK
| | - Neel Deferm
- Certara UK Limited, Level 2, Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK
| | - Gaurangkumar Patel
- Certara UK Limited, Level 2, Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK
| | | | - David B Turner
- Certara UK Limited, Level 2, Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK
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Wang Y, Jiang ZH, Zhou YW, Qiu TT, Wang H, Zhu MS, Chen X, Zhang XN. Gallbladder dysfunction caused by MYPT1 ablation triggers cholestasis-induced hepatic fibrosis in mice. Hepatol Commun 2024; 8:e0473. [PMID: 38934703 PMCID: PMC11213606 DOI: 10.1097/hc9.0000000000000473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 04/19/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown. METHODS Here, we established an animal model of gallbladder dysfunction and assessed the role of a diseased gallbladder in cholestasis-induced hepatic fibrosis (CIHF). RESULTS Mice with smooth muscle-specific deletion of Mypt1, the gene encoding the main regulatory subunit of myosin light chain phosphatase (myosin phosphatase target subunit 1 [MYPT1]), had apparent dysfunction of gallbladder motility. This dysfunction was evidenced by abnormal contractile responses, namely, inhibited cholecystokinin 8-mediated contraction and nitric oxide-resistant relaxation. As a consequence, the gallbladder displayed impaired bile filling and biliary tract dilation comparable to the alterations in CIHF. Interestingly, the mutant animals also displayed CIHF features, including necrotic loci by the age of 1 month and subsequently exhibited progressive fibrosis and hyperplastic/dilated bile ducts. This pathological progression was similar to the phenotypes of the animal model with bile duct ligation and patients with CIHF. The characteristic biomarker of CIHF, serum alkaline phosphatase activity, was also elevated in the mice. Moreover, we observed that the myosin phosphatase target subunit 1 protein level was able to be regulated by several reagents, including lipopolysaccharide, exemplifying the risk factors for gallbladder dysfunction and hence CIHF. CONCLUSIONS We propose that gallbladder dysfunction caused by myosin phosphatase target subunit 1 ablation is sufficient to induce CIHF in mice, resulting in impairment of the bile transport system.
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Affiliation(s)
- Ye Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
| | - Zhi-Hui Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
| | - Yu-Wei Zhou
- Jiangsu Key Laboratory of Molecular Medicine, Department of Otolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Tian-Tian Qiu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
| | - Han Wang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
| | - Min-Sheng Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
| | - Xin Chen
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
| | - Xue-Na Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, China
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China
- Jinling Pharmaceutical Co., Ltd., Nanjing, China
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Dahmiwal T, Zade A, Tote D, Reddy S, Sudabattula K. Dietary Considerations in Cholecystectomy: Investigating the Impact of Various Dietary Factors on Symptoms and Outcomes. Cureus 2024; 16:e61183. [PMID: 38933619 PMCID: PMC11200314 DOI: 10.7759/cureus.61183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
Cholecystectomy is commonly performed to address gallstone diseases, including the development of gallstones, which can lead to symptoms such as nausea, vomiting, and abdominal pain. Bile acids (BAs) produced by the liver are primarily stored and concentrated in the gallbladder (GB). After cholecystectomy, the body's ability to digest lipids is reduced due to the absence of the GB. Post-cholecystectomy syndrome (PCS) can occur when abdominal symptoms manifest after surgery. The purpose of this review is to look at the various effects of different dietary factors on patients undergoing cholecystectomy, how they affect their overall health after surgery, and how they contribute to symptoms of PCS. Some individuals may experience mild discomfort or alterations in bowel patterns, especially after consuming high-fat meals. The findings from the conducted studies suggest that, although dietary changes are a common recommendation, these measures are not sufficiently supported by evidence when it comes to alleviating symptoms and improving outcomes post-cholecystectomy. The studies found that subjects who consumed particular foods, such as processed meat and fried fatty foods, had exacerbated symptoms after cholecystectomy. Further studies are still required to understand the precise food factors that might affect post-surgical symptoms, as well as outcomes, and to develop tailored measures to enhance patient care and long-term prognosis after undergoing cholecystectomy.
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Affiliation(s)
- Tushar Dahmiwal
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Anup Zade
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Darshana Tote
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Srinivasa Reddy
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Kesav Sudabattula
- General Surgery, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Peng T, Zhou C, Zhang Z, Liu Y, Lin X, Ye Y, Zhong Y, Wang P, Jia Y. Review on bile dynamics and microfluidic-based component detection: Advancing the understanding of bilestone pathogenesis in the biliary tract. BIOMICROFLUIDICS 2024; 18:014105. [PMID: 38370511 PMCID: PMC10869170 DOI: 10.1063/5.0186602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/19/2024] [Indexed: 02/20/2024]
Abstract
Bilestones are solid masses found in the gallbladder or biliary tract, which block the normal bile flow and eventually result in severe life-threatening complications. Studies have shown that bilestone formation may be related to bile flow dynamics and the concentration level of bile components. The bile flow dynamics in the biliary tract play a critical role in disclosing the mechanism of bile stasis and transportation. The concentration of bile composition is closely associated with processes such as nucleation and crystallization. Recently, microfluidic-based biosensors have been favored for multiple advantages over traditional benchtop detection assays for their less sample consumption, portability, low cost, and high sensitivity for real-time detection. Here, we reviewed the developments in bile dynamics study and microfluidics-based bile component detection methods. These studies may provide valuable insights into the bilestone formation mechanisms and better treatment, alongside our opinions on the future development of in vitro lithotriptic drug screening of bilestones and bile characterization tests.
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Affiliation(s)
- Tao Peng
- Zhuhai UM Science & Technology Research Institute, Zhuhai, China
| | - Chenxiao Zhou
- Li Po Chun United World College of Hong Kong, Hong Kong, China
| | | | | | - Xiaodong Lin
- Zhuhai UM Science & Technology Research Institute, Zhuhai, China
| | - Yongqing Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yunlong Zhong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ping Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yanwei Jia
- Authors to whom correspondence should be addressed: and
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Xu F, Yu Z, Liu Y, Du T, Yu L, Tian F, Chen W, Zhai Q. A High-Fat, High-Cholesterol Diet Promotes Intestinal Inflammation by Exacerbating Gut Microbiome Dysbiosis and Bile Acid Disorders in Cholecystectomy. Nutrients 2023; 15:3829. [PMID: 37686860 PMCID: PMC10489946 DOI: 10.3390/nu15173829] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/21/2023] [Accepted: 08/30/2023] [Indexed: 09/10/2023] Open
Abstract
Patients with post-cholecystectomy (PC) often experience adverse gastrointestinal conditions, such as PC syndrome, colorectal cancer (CRC), and non-alcoholic fatty liver disease (NAFLD), that accumulate over time. An epidemiological survey further revealed that the risk of cholecystectomy is associated with high-fat and high-cholesterol (HFHC) dietary intake. Mounting evidence suggests that cholecystectomy is associated with disrupted gut microbial homeostasis and dysregulated bile acids (BAs) metabolism. However, the effect of an HFHC diet on gastrointestinal complications after cholecystectomy has not been elucidated. Here, we aimed to investigate the effect of an HFHC diet after cholecystectomy on the gut microbiota-BA metabolic axis and elucidate the association between this alteration and the development of intestinal inflammation. In this study, a mice cholecystectomy model was established, and the levels of IL-Iβ, TNF-α, and IL-6 in the colon were increased in mice fed an HFHC diet for 6 weeks. Analysis of fecal BA metabolism showed that an HFHC diet after cholecystectomy altered the rhythm of the BA metabolism by upregulating liver CPY7A1, CYP8B1, and BSEP and ileal ASBT mRNA expression levels, resulting in increased fecal BA levels. In addition, feeding an HFHC diet after cholecystectomy caused a significant dysbiosis of the gut microbiota, which was characterized by the enrichment of the metabolic microbiota involved in BAs; the abundance of pro-inflammatory gut microbiota and related pro-inflammatory metabolite levels was also significantly higher. In contrast, the abundance of major short-chain fatty acid (SCFA)-producing bacteria significantly decreased. Overall, our study suggests that an HFHC diet after cholecystectomy promotes intestinal inflammation by exacerbating the gut microbiome and BA metabolism dysbiosis in cholecystectomy. Our study also provides useful insights into the maintenance of intestinal health after cholecystectomy through dietary or probiotic intervention strategies.
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Affiliation(s)
- Fusheng Xu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Zhiming Yu
- Wuxi People’s Hospital Afliated to Nanjing Medical University, Wuxi 214023, China;
| | - Yaru Liu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Ting Du
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Leilei Yu
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Fengwei Tian
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
- National Engineering Research Center for Functional Food, Jiangnan University, Wuxi 214122, China
| | - Qixiao Zhai
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi 214122, China; (F.X.); (Y.L.); (T.D.); (L.Y.); (F.T.); (W.C.)
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
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Dellschaft N, Hoad C, Marciani L, Gowland P, Spiller R. Small bowel water content assessed by MRI in health and disease: a collation of single-centre studies. Aliment Pharmacol Ther 2022; 55:327-338. [PMID: 34716925 DOI: 10.1111/apt.16673] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/12/2021] [Accepted: 10/13/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND New developments in MRI have allowed the non-invasive, accurate measurement of the small bowel water content (SBWC). AIMS To collate studies measuring SBWC following ingestion of a range of foods in both health and disease to provide data for adequately powering future studies in this area. METHODS This collation brings together 29 studies including 954 participants (530 healthy, 54 diverticulosis, 255 IBS, 53 functional constipation, 12 cystic fibrosis, 15 Crohn's disease, 20 coeliac disease, 15 scleroderma) which have been carried out in a single centre using comparable study designs. RESULTS Fasting SBWC (mean 82 [SD 65] mL) shows high variability with a small decline with advancing age (healthy volunteers only; individual patient data). Fasting values are increased in untreated coeliac disease (202 [290] mL, P = 0.004). Post-prandial SBWC shows less intra-individual variability than fasting values in healthy volunteers. SBWC is increased by eating, most markedly by high fat meals but also by fibre, both viscous and particulate. Indigestible residue accumulates in late post-prandial period but empties soon after ingestion of a high calorie meal which produces a significant drop (by 50 [52] mL) in healthy volunteers. The associated fall in SBWC is abnormal in people with cystic fibrosis (SBWC reduced by 10 [121] mL, P = 0.002) and in people with irritable bowel syndrome with diarrhoea (SBWC reduced by 17 [43] mL, P = 0.007). CONCLUSIONS SBWC as assessed by MRI is a valuable biomarker indicating the balance of secretion and absorption in health and disease and the impact of treatments.
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Affiliation(s)
- Neele Dellschaft
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Caroline Hoad
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Luca Marciani
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Penny Gowland
- Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Robin Spiller
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK.,Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
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7
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Abstract
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.
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Mast cell infiltration and activation in the gallbladder wall: Implications for the pathogenesis of functional gallbladder disorder in adult patients. Ann Diagn Pathol 2021; 54:151798. [PMID: 34391170 DOI: 10.1016/j.anndiagpath.2021.151798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 07/14/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Functional gallbladder disorder (FGD) is characterized by recurrent biliary colic with a decreased gallbladder ejection fraction on cholescintigraphy but absence of visible gallbladder abnormalities on ultrasonography. FGD is generally regarded as a primary gallbladder motility disturbance, however, the underlying pathophysiology remains largely unknown. In this study, we investigated the potential role of mast cells in the pathogenesis of FGD by examining mast cell density and activation in the gallbladder wall. DESIGN Twenty adult patients with FGD undergoing cholecystectomy were included in the study. Seven patients with no gallbladder disease were served as controls who were subject to incidental cholecystectomy during abdominal surgery such as partial hepatectomy. The density of mast cells in the gallbladder wall was assessed by immunohistochemistry and by toluidine blue special stain. Mast cell activation was evaluated by calculating the percentage of degranulated mast cells on toluidine blue stain. RESULTS Compared to the controls, patients with FGD showed a significant increase in mast cell infiltration in the gallbladder walls. Peak mast cell accumulation was predominantly located in the inner muscular layer of the gallbladder wall. Mast cell activation was also markedly increased in the FGD group as evidenced by significantly enhanced mast cell degranulation. CONCLUSIONS Mast cell infiltration and activation were significantly increased in the muscular wall of gallbladders from FGD patients, suggesting potential involvement of mast cells in the compromised gallbladder motility in adult patients with FGD.
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Meessen EC, Bakker GJ, Nieuwdorp M, Dallinga-Thie GM, Kemper EM, Olde Damink SW, Romijn JA, Hartmann B, Holst JJ, Knop FK, Groen AK, Schaap FG, Soeters MR. Parenteral nutrition impairs plasma bile acid and gut hormone responses to mixed meal testing in lean healthy men. Clin Nutr 2021; 40:1013-1021. [DOI: 10.1016/j.clnu.2020.06.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/17/2020] [Accepted: 06/27/2020] [Indexed: 01/06/2023]
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10
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Stamatopoulos K, Pathak SM, Marciani L, Turner DB. Population-Based PBPK Model for the Prediction of Time-Variant Bile Salt Disposition within GI Luminal Fluids. Mol Pharm 2020; 17:1310-1323. [DOI: 10.1021/acs.molpharmaceut.0c00019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
| | - Shriram M. Pathak
- Certara Ltd (Simcyp Division), Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, United Kingdom
| | - Luca Marciani
- Nottingham Digestive Diseases Centre and National Institute for Health Research, Biomedical Research Unit, Nottingham University Hospitals, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - David B. Turner
- Certara Ltd (Simcyp Division), Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, United Kingdom
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A Gallbladder-Based Enterohepatic Circulation Model for Pharmacokinetic Studies. Eur J Drug Metab Pharmacokinet 2018; 44:493-504. [PMID: 30488336 DOI: 10.1007/s13318-018-0535-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND AND OBJECTIVES Strategies for modeling the enterohepatic circulation (EHC) process reported in the literature vary; however, gallbladder-based models currently provide the best physiological representation of the process. Regardless, the addition of a gallbladder to the model does not fully depict the physiology of EHC. A more physiological gallbladder-based EHC model is needed. This model should take into account a physiological representation of the bile secretion, gallbladder filling and emptying, the duration of gallbladder emptying, and irregular mealtimes. Considering all of these factors, the objectives of the present analysis were to propose a gallbladder-based EHC model and then to use that model to perform sensitivity analyses evaluating the effect of the extent of EHC on the pharmacokinetic profile and noncompartmental analysis (NCA) calculations. METHODS A gallbladder-based model that describes the EHC process was developed and used to perform determinant simulations assuming various degrees of EHC. Next, these simulations were compared to evaluate the effect of the EHC on the pharmacokinetic profiles of orally administered drugs. The influence of the EHC process on the NCA calculations was determined while assuming two sampling schemes that differed in the times at which sampling was performed in relation to meal times. RESULTS The presence of EHC results in nonlinearity in the system and changes the pharmacokinetic profile, affecting the maximum concentration (Cmax), time to Cmax (Tmax), and half-life estimates. Comparison of the results obtained using the two sampling schemes for a drug undergoing various degrees of EHC demonstrated a significant influence of the selected sampling times on the NCA estimations. Bias in the NCA calculations was also dependent on the sampling times used. CONCLUSION Caution should be taken when designing clinical studies for drugs that undergo EHC. It may be essential to consider the timing of meals when planning pharmacokinetic studies and defining sampling times. The period over which samples are taken needs to be extended as compared to that traditionally used with other drugs. Future studies that attempt to identify the best sampling strategies in the presence of EHC are needed.
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Hosapatna M, Souza AD, Ankolekar VH. Development of the Gall Bladder, and Caudate and Quadrate Lobes of the Liver: A Fetal Morphometric Study. Kurume Med J 2018; 65:31-35. [PMID: 30449825 DOI: 10.2739/kurumemedj.ms652003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
INTRODUCTION The gall bladder (GB) is a storage reservoir that allows bile acids to be delivered in a high concentration. The quadrate (QL) and caudate lobes (CL) are functional parts of the liver. The knowledge of the gross and developmental anatomy of GB and CL and QL of liver is important for surgeons who operate in this region. The present study was conducted to examine the developmental sequence and morphometry of the GB, and CL and QL of liver. MATERIALS AND METHODS In the present cross sectional study the parameters measured were length of GB from the neck to the lowest point on the fundus, and the length and width of QL and CL measured at the midpoint. The data was analyzed statistically and the various parameters were correlated using Pearson's correlation. RESULTS There was a statistically significant correlation indicating that the growth of GB, QL and CL was proportional to the gestational age (GA). The variations in the morphology of the GB were also noted. In two specimens it was found that the GB was embedded partially in the substance of the liver and failed to reach the inferior border of the liver. CONCLUSION The regression equations calculated in the study provide a tool to estimate the lengths of GB, QL and CL prenatally.
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Affiliation(s)
- Mamatha Hosapatna
- Department of Anatomy, Kasturba Medical College, Manipal Academy of Higher Education
| | - Anne D Souza
- Department of Anatomy, Kasturba Medical College, Manipal Academy of Higher Education
| | - Vrinda Hari Ankolekar
- Department of Anatomy, Kasturba Medical College, Manipal Academy of Higher Education
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Su F, He E, Qian L, Zhu Z, Wei L, Zeng Z, Qu W, Xu R, Yi Z. Complication Follow-up With Ultrasonographic Analyses of 91 Cases With Donor Gallbladder Preservation in Living Donor Liver Transplantation of Left Lateral Sectionectomies. Transplant Proc 2018; 50:217-221. [PMID: 29407312 DOI: 10.1016/j.transproceed.2017.12.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 10/22/2017] [Accepted: 12/05/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Preserving the donor's gallbladder during living donor liver transplantation (LDLT) is a better method for liver transplantation surgery, but not enough is known about gallbladder complications after the operation. METHODS We retrospectively investigated postsurgical donor gallbladder complications in clinical LDLT with gallbladder preservation. The feasibility of retaining the gallbladder during liver graft procurement is discussed. Ninety-one donors with retained gallbladder after LDLT with the hepatic left lateral sectionectomy (from June 2013 to October 2015) were retrospectively analyzed. Donors were followed for 12.6 to 40.7 months after surgery (median 26.1 months). Sonography was used to evaluate gallbladder characteristics before and after surgery. RESULTS Gallbladder function had recovered to almost normal 1 month after transplantation. Four donors (4.40%) experienced gallbladder enlargement that resolved after 3 days. Thickening of the gallbladder wall in 31 donors (34.07%) was restored within 2 to 75 days. Biliary sludge appeared in 9 donors (9.89%); 6 of them recovered within 3 to 34 days. Three (3.30%) and 1 donor (1.10%) suffered gallstone and gallbladder polyps, respectively, which persisted until the last follow-up. CONCLUSION The rate of postoperative complications of the gallbladder in donors was relative low. Preserving the gallbladder in liver transplantation donors during liver graft procurement is feasible and safe.
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Affiliation(s)
- F Su
- Department of Ultrasound, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - E He
- Department of Ultrasound, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - L Qian
- Department of Ultrasound, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China.
| | - Z Zhu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - L Wei
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Z Zeng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - W Qu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - R Xu
- Department of Ultrasound, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
| | - Z Yi
- Department of Ultrasound, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing, China
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Romański KW, Nicpoń J. Occurrence of the specific long spike burst pattern in the ovine proximal gallbladder as an indication of myoelectric regional variability. Onderstepoort J Vet Res 2018; 85:e1-e8. [PMID: 29943583 PMCID: PMC6238780 DOI: 10.4102/ojvr.v85i1.1455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 10/19/2017] [Accepted: 03/16/2018] [Indexed: 11/12/2022] Open
Abstract
The myoelectrical activity of the ovine gallbladder has not been fully recognised. Five rams were fitted with six small intestinal and three gallbladder electrodes and a strain gauge force transducer was mounted near the gallbladder fundic electrode. In two series of successive experiments, the electromyographical and mechanical recordings were recorded over a period of 5–7 hours. The occurrence of the slow waves in the small bowel was regular, unlike those in the gallbladder. In the gallbladder infundibulum, the specific pattern, called the long spike burst pattern (LSBP), was observed. It comprised usually one or two parts of prolonged duration. The first part resembled the classical (short lasting) spike burst in the small bowel, and its amplitude was lower than that of the second part. The spike burst frequency of the second part was 2–3 times lower than that of the first part. During phase 1-like and phase 2a-like activities, the intensity of the gallbladder LSBP was reduced while enhanced after feeding. In fasted rams, the duration of a specific pattern, observed in the gallbladder infundibulum, was longer than in non-fasted animals and its amplitude was low. Similar events were recorded in the gallbladder corpus, but the specific pattern was shorter and irregular. In the gallbladder fundus, mostly irregular short spike bursts were recorded. It is concluded that in sheep, specific types of the long-lasting groups of spikes occur in the upper gallbladder areas exhibiting myoelectrical regional variability. The character of an LSBP depends on feeding conditions.
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Affiliation(s)
- Krzysztof W Romański
- Centre for Experimental Diagnostics and Biomedical Innovations, Wrocław University of Environmental and Life Sciences.
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15
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Żulpo M, Balbus J, Kuropka P, Kubica K. A model of gallbladder motility. Comput Biol Med 2018; 93:139-148. [DOI: 10.1016/j.compbiomed.2017.12.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 12/10/2017] [Accepted: 12/20/2017] [Indexed: 10/18/2022]
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Seljetun KO, Eliassen E, Karinen R, Moe L, Vindenes V. Quantitative method for analysis of six anticoagulant rodenticides in faeces, applied in a case with repeated samples from a dog. Acta Vet Scand 2018; 60:3. [PMID: 29343296 PMCID: PMC5772691 DOI: 10.1186/s13028-018-0357-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 01/10/2018] [Indexed: 11/21/2022] Open
Abstract
Background Accidental poisoning with anticoagulant rodenticides is not uncommon in dogs, but few reports of the elimination kinetics and half-lives in this species have been published. Our objectives were to develop and validate a new method for the quantification of anticoagulant rodenticides in canine blood and faeces using reversed phase ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) and apply the method on a case of anticoagulant rodenticide intoxication. Results Sample preparation was liquid–liquid extraction. Six anticoagulant rodenticides were separated using a UPLC® BEH C18-column with a mobile phase consisting of 5 mM ammonium formate buffer pH 10.2 and methanol. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions. The limits of quantification were set at the levels of the lowest calibrator (1.5–2.7 ng/mL or ng/g). The method was successfully applied to a case from a dog accidentally poisoned with anticoagulant rodenticide. Coumatetralyl and brodifacoum concentrations were determined from serial blood and faecal samples. A terminal half-life of at least 81 days for coumatetralyl in blood was estimated, which is longer than previous reported in other species. A slow elimination of brodifacoum from the faeces was found, with traces still detectable in the faeces at day 513. Conclusions This study offers a new method of detection and quantification of six frequently used anticoagulant rodenticides in canine faeces. Such drugs might cause serious health effects and it is important to be able to detect these drugs, to initiate proper treatment. The very long elimination half-lives detected in our study is important to be aware of in assessment of anticoagulant rodenticide burden to the environment.
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Okour M, Jacobson PA, Ahmed MA, Israni AK, Brundage RC. Mycophenolic Acid and Its Metabolites in Kidney Transplant Recipients: A Semimechanistic Enterohepatic Circulation Model to Improve Estimating Exposure. J Clin Pharmacol 2018; 58:628-639. [PMID: 29329489 DOI: 10.1002/jcph.1064] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 11/19/2017] [Indexed: 01/13/2023]
Abstract
Mycophenolic acid (MPA) is an approved immunosuppressive agent widely prescribed to prevent rejection after kidney transplantation. Wide between-subject variability (BSV) in MPA exposure exists which in part may be due to variability in enterohepatic recirculation (EHC). Several modeling strategies were developed to evaluate EHC as part of MPA pharmacokinetics, however mechanistic representation of EHC is limited. These models have not provided a satisfactory representation of the physiology of EHC in their modeling assumptions. The aim of this study was i) to develop an integrated model of MPA (total and unbound) and its metabolites (MPAG and acyl-MPAG) in kidney recipients, where this model provides a more physiological representation of EHC process, and ii) to evaluate the effect of donor and recipient clinical covariates and genotypes on MPA disposition. A five-compartment model with first-order input into an unbound MPA compartment connected to the MPAG, acyl-MPAG, and gallbladder compartment best fit the data. To represent the EHC process, the model was built based on the physiological concepts related to the hepatobiliary system and the gallbladder filling and emptying processes. The effect of cyclosporine versus tacrolimus on clearance of unbound MPA was included in the base model. Covariate analysis showed creatinine clearance to be significant on oral clearance of unbound MPA. The hepatic nuclear factor 1 alpha (HNF1A) genetic single nucleotide polymorphism (SNP) (rs2393791) in the recipient significantly affected the fraction of enterohepatically-circulated drug. Oral clearance of MPAG was affected by recipient IMPDH1 SNP (rs2288553), diabetes at the time of transplant, and donor sex.
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Affiliation(s)
- Malek Okour
- Clinical Pharmacology Modeling and Simulation (CPMS), GlaxoSmithKline, King of Prussia, PA, USA
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
| | - Mariam A Ahmed
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
| | - Ajay K Israni
- Department of Medicine, Department of Epidemiology and Community Health, Hennepin County Medical Center and University of Minnesota, Minneapolis, MN, USA
| | - Richard C Brundage
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA
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Romański K, Nicpoń J. The specific long spike burst pattern indicates the presence of regional variability in the ovine gallbladder motor function. Biologia (Bratisl) 2017. [DOI: 10.1515/biolog-2017-0170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Abdallah E, Emile SH, Elfeki H, Fikry M, Abdelshafy M, Elshobaky A, Elgendy H, Thabet W, Youssef M, Elghadban H, Lotfy A. Role of ursodeoxycholic acid in the prevention of gallstone formation after laparoscopic sleeve gastrectomy. Surg Today 2017; 47:844-850. [PMID: 27837275 DOI: 10.1007/s00595-016-1446-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 10/28/2016] [Indexed: 01/23/2023]
Abstract
PURPOSE Postoperative cholelithiasis (CL) is a latent complication of bariatric surgery. The aim of this study was to evaluate the role of ursodeoxycholic acid (UDCA) in the prevention of CL after laparoscopic sleeve gastrectomy (LSG). METHODS This was a retrospective analysis of the prospectively collected data of patients with morbid obesity who underwent LSG. Patients were subdivided into two groups: Group I, which did not receive prophylactic treatment with UCDA after LSG; and Group II, which received UCDA therapy for 6 months after LSG. Patients' characteristics, operation duration, weight loss data, and incidence of CL at 6 and 12 months postoperatively were collected. RESULTS A total of 406 patients (124 males, 282 females) with a mean age of 32.1 ± 9.4 years were included. The mean baseline body mass index (BMI) was 50.1 ± 8.3 kg/m2. Group I comprised 159 patients, and Group II comprised 247 patients. The two groups showed comparable demographics, % excess weight loss (EWL), and decrease in BMI at 6 and 12 months after LSG. Eight patients (5%) developed CL in Group I, whereas no patients in Group II did (P = 0.0005). Preoperative dyslipidemia and rapid loss of excess weight within the first 3 months after LSG were the risk factors that significantly predicted CL postoperatively. CONCLUSION The use of UCDA effectively reduced the incidence of CL after LSG in patients with morbid obesity. Dyslipidemia and rapid EWL in the first 3 months after LSG significantly predisposed patients to postoperative CL.
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Affiliation(s)
- Emad Abdallah
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Sameh Hany Emile
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt.
| | - Hossam Elfeki
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Mohamed Fikry
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Mahmoud Abdelshafy
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Ayman Elshobaky
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Hesham Elgendy
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Waleed Thabet
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Mohamed Youssef
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Hosam Elghadban
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
| | - Ahmed Lotfy
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University Hospitals, Elgomhuoria Street, Mansoura, Egypt
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Steingoetter A, Radovic T, Buetikofer S, Curcic J, Menne D, Fried M, Schwizer W, Wooster TJ. Imaging gastric structuring of lipid emulsions and its effect on gastrointestinal function: a randomized trial in healthy subjects. Am J Clin Nutr 2015; 101:714-24. [PMID: 25833970 DOI: 10.3945/ajcn.114.100263] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Accepted: 01/14/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Efficient fat digestion requires fat processing within the stomach and fat sensing in the intestine. Both processes also control gastric emptying and gastrointestinal secretions. OBJECTIVE We aimed to visualize the influence of the intragastric stability of fat emulsions on their dynamics of gastric processing and structuring and to assess the effect this has on gastrointestinal motor and secretory functions. DESIGN Eighteen healthy subjects with normal body mass index (BMI) were studied on 4 separate occasions in a double-blind, randomized, crossover design. Magnetic resonance imaging (MRI) data of the gastrointestinal tract and blood triglycerides were recorded before and for 240 min after the consumption of the following 4 different fat emulsions: lipid emulsion 1 (LE1; acid stable, 0.33 μm), lipid emulsion 2 (LE2; acid stable, 52 μm), lipid emulsion 3 (LE3; acid unstable, solid fat, 0.32 μm), and lipid emulsion 4 (LE4; acid unstable, liquid fat, 0.38 μm). RESULTS Intragastric emulsion instability was associated with a change in gastric emptying. Acid-unstable emulsions exhibited biphasic and faster emptying profiles than did the 2 acid-stable emulsions (P ≤ 0.0001). When combined with solid fat (LE3), different dynamics of postprandial gallbladder volume were induced (P ≤ 0.001). For acid-stable emulsions, a reduction of droplet size by 2 orders of magnitude [LE1 (0.33 μm) compared with LE2 (52 μm)] delayed gastric emptying by 38 min. Although acid-stable (LE1 and LE2) and redispersible (LE4) emulsions caused a constant increase in blood triglycerides, no increase was detectable for LE3 (P < 0.0001). For LE3, MRI confirmed the generation of large fat particles during gastric processing, which emptied into and progressed through the small intestine. CONCLUSIONS MRI allows the detailed characterization of the in vivo fate of lipid emulsions. The acute effects of lipid emulsions on gastric emptying, gallbladder volume, and triglyceride absorption are dependent on microstructural changes undergone during consumption. Gastric peristalsis and secretion were effective at redispersing pools of liquid fat in the stomach. This trial was registered at clinicaltrials.gov as NCT01253005.
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Affiliation(s)
- Andreas Steingoetter
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
| | - Tijana Radovic
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
| | - Simon Buetikofer
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
| | - Jelena Curcic
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
| | - Dieter Menne
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
| | - Michael Fried
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
| | - Werner Schwizer
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
| | - Tim J Wooster
- From the Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland (AS, TR, SB, JC, MF, and WS); the Institute for Biomedical Engineering, University and Federal Institute of Technology Zurich, Zurich, Switzerland (AS); Menne Biomed Consulting, Tübingen, Germany (DM); the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Preventive Health Flagship, Werribee, Australia (TJW); and the Nestlé Research Centre, Vers Chez les Blancs, Switzerland (TJW)
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Micucci M, Ioan P, Aldini R, Cevenini M, Alvisi V, Ruffilli C, Chiarini A, Budriesi R. Castanea sativa Mill. extract contracts gallbladder and relaxes sphincter of Oddi in guinea pig: a natural approach to biliary tract motility disorders. J Med Food 2014; 17:795-803. [PMID: 24654975 DOI: 10.1089/jmf.2013.0090] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Impaired gallbladder motility is a contributing factor to gallstone formation. Since many drugs delaying intestinal motility inhibit gallbladder emptying, the aim of the present study was to evaluate the effect on gallbladder and sphincter of Oddi motility of a Natural Chestnut Wood Extract (NEC) that reduces intestinal motility. In order to evaluate the effect of the extract in normal- and high-risk gallstone conditions, the investigation was performed using tissues from animals fed normal and lithogenic diet. Fifty guinea pigs were administered either control or lithogenic diet. The spontaneous motility of the gallbladder and sphincter of Oddi were recorded on isolated gallbladder tissues; thereafter, the effect of NEC on motility was tested and compared with carbachol (CCh), potassium chloride (KCl), noradrenaline (NA), and A71623. Compared to controls, the lithogenic diet induced an irregular and disordered motor pattern in both the gallbladder and sphincter of Oddi. NEC increased gallbladder and decreased sphincter of Oddi spontaneous motility independently of cholinergic, adrenergic, and CCK-1 receptor-mediated pathways both in controls and in lithogenic diet-fed animals, although the effect was lower in the latter group. The effect was reversible and mediated by calcium channels. The natural extract of chestnut increasing gallbladder contraction and inducing the relaxation of the sphincter of Oddi can be of benefit in pathological conditions associated with increased transit time at risk of gallstones.
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Affiliation(s)
- Matteo Micucci
- 1 Dipartimento di Farmacia e Biotecnologie, Università di Bologna , Bologna, Italy
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Matsson EM, Eriksson UG, Palm JE, Artursson P, Karlgren M, Lazorova L, Brännström M, Ekdahl A, Dunér K, Knutson L, Johansson S, Schützer KM, Lennernäs H. Combined in vitro-in vivo approach to assess the hepatobiliary disposition of a novel oral thrombin inhibitor. Mol Pharm 2013; 10:4252-62. [PMID: 24079718 DOI: 10.1021/mp400341t] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Two clinical trials and a large set of in vitro transporter experiments were performed to investigate if the hepatobiliary disposition of the direct thrombin inhibitor prodrug AZD0837 is the mechanism for the drug-drug interaction with ketoconazole observed in a previous clinical study. In Study 1, [(3)H]AZD0837 was administered to healthy male volunteers (n = 8) to quantify and identify the metabolites excreted in bile. Bile was sampled directly from the jejunum by duodenal aspiration via an oro-enteric tube. In Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics of AZD0837, the intermediate metabolite (AR-H069927), and the active form (AR-H067637) was investigated (n = 17). Co-administration with ketoconazole elevated the plasma exposure to AZD0837 and the active form approximately 2-fold compared to placebo, which may be explained by inhibited CYP3A4 metabolism and reduced biliary clearance, respectively. High concentrations of the active form was measured in bile with a bile-to-plasma AUC ratio of approximately 75, indicating involvement of transporter-mediated excretion of the compound. AZD0837 and its metabolites were further investigated as substrates of hepatic uptake and efflux transporters in vitro. Studies in MDCK-MDR1 cell monolayers and P-glycoprotein (P-gp) expressing membrane vesicles identified AZD0837, the intermediate, and the active form as substrates of P-gp. The active form was also identified as a substrate of the multidrug and toxin extrusion 1 (MATE1) transporter and the organic cation transporter 1 (OCT1), in HEK cells transfected with the respective transporter. Ketoconazole was shown to inhibit all of these three transporters; in particular, inhibition of P-gp and MATE1 occurred in a clinically relevant concentration range. In conclusion, the hepatobiliary transport pathways of AZD0837 and its metabolites were identified in vitro and in vivo. Inhibition of the canalicular transporters P-gp and MATE1 may lead to enhanced plasma exposure to the active form, which could, at least in part, explain the clinical interaction with ketoconazole.
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Affiliation(s)
- Elin M Matsson
- Department of Pharmacy, Uppsala University , Box 580, SE-751 23 Uppsala, Sweden
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Effects of various food ingredients on gall bladder emptying. Eur J Clin Nutr 2013; 67:1182-7. [PMID: 24045793 PMCID: PMC3898429 DOI: 10.1038/ejcn.2013.168] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 07/19/2013] [Accepted: 07/26/2013] [Indexed: 12/17/2022]
Abstract
Background/objectives: The emptying of the gall bladder in response to feeding is pivotal for the digestion of fat, but the role of various food ingredients in contracting the gall bladder postprandially is not well understood. We hypothesized that different food ingredients, when consumed, will have a different effect on stimulating gall bladder emptying. To investigate this we designed two randomized, investigator-blind, cross-over studies in healthy subjects using magnetic resonance imaging (MRI) to measure gall bladder volumes serially and non-invasively. Subjects/methods: Study 1: exploratory study evaluating the effects of 10 different food ingredients on gall bladder emptying in eight healthy subjects. The choice of ingredients varied from common items like coffee, tea and milk to actives like curcumin and potato protease inhibitor. Study 2: mechanistic study investigating the cholecystokinin (CCK) dose response to the best performer ingredient from Study 1 in 21 healthy subjects four ways. Results: The largest gall bladder volume change in Study 1 was observed with fat, which therefore became the dose-response ingredient in Study 2, where the maximum % gall bladder volume change correlated well with CCK. Conclusions: These serial test-retest studies showed that the fasted gall bladder volume varied remarkably between individuals and that individual day-to-day variability had wide coefficients of variation. Improved knowledge of how to stimulate bile release using food ingredients will be useful to improve in vitro–in vivo correlation of bioavailability testing of hydrophobic drugs. It could improve performance of cholesterol-lowering plant stanol and sterol products and possibly aid understanding of some cholesterol gallstone disease.
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Computational analysis of the flow of bile in human cystic duct. Med Eng Phys 2012; 34:1177-83. [DOI: 10.1016/j.medengphy.2011.12.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 12/05/2011] [Accepted: 12/08/2011] [Indexed: 01/20/2023]
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Wittenburg H, Tennert U, Mössner J. [Hormonal and metabolic functions of the small intestine]. Internist (Berl) 2010; 51:695-701. [PMID: 20383479 DOI: 10.1007/s00108-009-2564-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The small intestine exhibits numerous hormonal and metabolic functions. These are mediated by enteroendocrine cells that are expressed in addition to enterocytes in the mucosa of the small intestine. The release of cholecystokinin causes the secretion of pancreatic enzymes and a contraction of the gallbladder. Recently, a hormonal regulation of gallbladder filling was confirmed. This is mediated by the hormone FGF15/19 which is secreted by enterocytes of the terminal ileum following induction of its expression by bile acids. In addition, FGF15/19 reduces synthesis of bile acids and fatty acids and inhibits gluconeogenesis. Ghrelin is the only intestinal hormone that increases food intake. Contrary, a number of hormones such as cholecystokinin and glucagon-like peptide are expressed in the small intestine and mediate satiation. Knowledge of the intestinal hormones and their functions is important for the full understanding of metabolic control and provides targets for innovative therapy of several diseases such as diabetes type 2, non-alcoholic steatohepatitis and obesity.
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Affiliation(s)
- H Wittenburg
- Department für Innere Medizin, Neurologie und Dermatologie, Klinik und Polklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig AöR, Liebigstrasse 20, Leipzig, Germany.
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Al-Atabi M, Chin SB, Luo XY. Experimental Investigation of the Flow of Bile in Patient Specific Cystic Duct Models. J Biomech Eng 2010; 132:041003. [DOI: 10.1115/1.4001043] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Three-dimensional scaled-up transparent models of three human cystic ducts were prepared on the basis of anatomical specimens. The measurement of pressure drop across the cystic duct models and visualization of the flow structures within these ducts were performed at conditions replicating the physiological state. The flow visualization study confirmed the laminar nature of the flow of bile inside the cystic duct and values of pressure drop coefficient (Cp) decreased as the Reynolds number (Re) increased. The three tested models showed comparable behavior for the curve of Reynolds number versus the pressure drop coefficient. The results show that the tested cystic ducts have both increased pressure drop and complicated flow structures when compared with straight conduits. High resistance in a cystic duct may indicate that the gallbladder has to exert large force in expelling bile to the cystic duct. For patients with diseased gallbladder, and even in healthy persons, gallbladder is known to stiffen with age and it may lose its compliance or flexibility. A high resistance cystic duct coupled with a stiffened gallbladder may result in prolonged stasis of bile in the gallbladder, which is assumed to encourage the formation of gallstones.
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Affiliation(s)
- Mushtak Al-Atabi
- School of Engineering, Taylor’s University College, Selangor, 47500, Malaysia
| | - S. B. Chin
- Department of Mechanical Engineering, University of Sheffield, Sheffield S1 3JD, UK
| | - X. Y. Luo
- Department of Mathematics, University of Glasgow, Glasgow G12 8QW, UK
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Lehr T, Staab A, Tillmann C, Trommeshauser D, Schaefer HG, Kloft C. A Quantitative Enterohepatic Circulation Model. Clin Pharmacokinet 2009; 48:529-42. [DOI: 10.2165/11313370-000000000-00000] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Çerçi SS, Özbek FM, Çerçi C, Baykal B, Eroğlu HE, Baykal Z, Yıldız M, Sağlam S, Yeşildağ A. Gallbladder function and dynamics of bile flow in asymptomatic gallstone disease. World J Gastroenterol 2009; 15:2763-7. [PMID: 19522027 PMCID: PMC2695892 DOI: 10.3748/wjg.15.2763] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of gallbladder stones on motor functions of the gallbladder and the dynamics of bile flow in asymptomatic gallstone disease.
METHODS: Quantitative hepatobiliary scintigraphy was performed to detect the parameters of gallbladder motor function [gallbladder ejection fraction (GBEF), gallbladder visualization time (GBVT), gallbladder time to peak activity (GBTmax), gallbladder half emptying time (GBT1/2), and transit time of bile to duodenum (TTBD)] in 24 patients with asymptomatic cholelithiasis who were diagnosed incidentally during routine abdominal ultrasonographic examination and 20 healthy subjects with normal gallbladder.
RESULTS: Even though there was no significant difference in the clinical and laboratory parameters between the patient and control groups, all parameters of gallbladder function except TTBD were found to differ significantly between the two groups. GBEF in the patient group was decreased (P = 0.000) and GBVT, GBTmax, GBT1/2 in the patient group were longer (P = 0.000, P = 0.015, P = 0.001, respectively).
CONCLUSION: Our results showed that even if there were not any clinical and laboratory findings, gallbladder filling and emptying could be impaired in patients with gallstone disease.
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Xiao Y, Yu BP, Wu ZX, Yu Z. Effects of cholecystokinin on gallbladder muscle stripes of guinea pigs with cholesterol gallstone in vitro. Shijie Huaren Xiaohua Zazhi 2008; 16:2280-2284. [DOI: 10.11569/wcjd.v16.i20.2280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To establish an animal model of cholesterol stone and to explore the effects of cholecystokinin (CCK) on gallbladder muscle stripes of guinea pigs with cholesterol stone in vitro as well as to investigate the role of biliary kinetics in cholesterol stone formation.
METHODS: The animal model of cholesterol stone was established by feeding guinea pig with stone-leading forage. The guinea pigs were assigned to four groups: group A (the normal guinea pigs), group B (stone-leading forage for 4 wk), group C (stone-leading forage for 8 wk), and group D (the normal guinea pigs with injury of interstitial cell of cajal (ICC). Effects of 10-9, 10-8 and 10-7 mol/L cholecystokinin (CCK) on gallbladder muscle stripes of guinea pigs in vitro among the four groups were recorded and analyzed.
RESULTS: No cholesterol stone was observed in group A, and a total of 13 cases of cholesterol stone were observed in group B and C. The amplitude of contraction showed a dose-independent relationship with CCK-8 in groups A, B and C. Compared with group A, there was statistically significant diffference in group B and group C (P < 0.05). The contraction of smooth muscle was nearly abolished when interstitial cells of Cajal were destroyed using methylene blue incubation and intensive illumination. Although CCK was administered, there was no significant difference in the amplitude of the contraction of smooth muscle strip in group D (10-9 mol/L: 0.461 ± 0.071 vs 1.461 ± 0.252; 10-8 mol/L: 0.608 ± 0.118 vs 2.484 ± 0.283; 10-7 mol/L: 0.641 ± 0.129 vs 3.312 ± 0.311, all P < 0.01).
CONCLUSION: Muscular tension is significantly inhibited following injury of interstitial cells of Cajal. The damage of interstitial cells of Cajal may be an important factor related to cholelithiasis.
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A comparison of Roux-en-Y and Billroth-I reconstruction after laparoscopy-assisted distal gastrectomy. Ann Surg 2008; 247:962-7. [PMID: 18520223 DOI: 10.1097/sla.0b013e31816d9526] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The present study evaluated the efficacy of Roux-en-Y (R-Y) reconstruction and Billroth-I (B-I) reconstruction after laparoscopy-assisted distal gastrectomy (LADG). PATIENTS AND METHODS Between October 2000 and February 2006, a total of 133 consecutive patients who underwent LADG for gastric carcinoma were classified into 2 groups according to reconstruction (B-I, n = 65; R-Y, n = 68). Parameters analyzed included patients and tumor characteristics, operative details, postoperative outcomes, and nourishment state. Endoscopic findings of the gastric remnant and lower esophagus were evaluated at 12 months postoperatively. RESULTS Regarding postoperative complications, no significant differences were found between groups. In the B-I group, 3 patients developed anastomotic leakage and 4 patients suffered anastomotic stricture requiring endoscopic balloon dilation. So-called functional stasis after R-Y reconstruction was not found in this study. Incidence of heartburn at 12 months postoperatively was 37% in the B-I group and 8% in the R-Y group (P = 0.0002). Amount of meal consumed compared with preoperative value at 12 months postoperatively was significantly higher for the R-Y group than for the B-I group (83.6% +/- 15.3% vs. 77.8% +/- 16.0%; P = 0.047). Endoscopic findings showed that incidence of remnant gastritis was significantly lower in the R-Y group than in the B-I group (12% vs. 34%; P = 0.002). Bile reflux into the remnant stomach was not observed in the R-Y group. CONCLUSION R-Y reconstruction seems superior to B-I reconstruction for preventing both bile reflux into the gastric remnant and postoperative complications. We consider R-Y reconstruction as a feasible and safe method for LADG.
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Ramstedt KL, Center SA, Randolph JF, Yeager AE, Erb HN, Warner KL. Changes in gallbladder volume in healthy dogs after food was withheld for 12 hours followed by ingestion of a meal or a meal containing erythromycin. Am J Vet Res 2008; 69:647-51. [DOI: 10.2460/ajvr.69.5.647] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Yaylali OT, Yilmaz M, Kiraç FS, Degirmencioglu S, Akbulut M. Scintigraphic evaluation of gallbladder motor functions in H pylori positive and negative patients in the stomach with dyspepsia. World J Gastroenterol 2008; 14:1406-10. [PMID: 18322956 PMCID: PMC2693690 DOI: 10.3748/wjg.14.1406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the relationship between gallbladder (GB) motor function and H pylori infection in the stomach.
METHODS: All cases (86) underwent the 14C urea breath test (UBT). 14C-UBT was found as positive in 58 and negative in 28 dyspeptic patients. 14C- UBT was accepted as a gold standard test. Clo test and histopathologic examination were compared with the results of 14C-UBT in cases who tolerated upper gastrointestinal endoscopy procedure. Cholescintigraphy with 99mTc-mebrofenin was used to determine the parameters of GB motor function (GB filling and emptying time, half of the emptying time, ejection fraction at 30th and 60th min) in all patients.
RESULTS: We found the sensitivity and specificity as 88% and 86% for Clo test and as 89% and 80% for histologic evaluation, respectively. The parameters of GB function were not significantly different in H pylori positive and negative patients. The GB emptying was normal in both groups. Minimum GB filling time was 30 min in 34 of 86 cases (39.5%), filling was not observed in 2 cases. The GB ultrasonography (USG) results were normal for all cases and bile composition abnormality was not determined.
CONCLUSION: Our study showed that 14C-UBT is highly reliable method to detect the presence of H pylori. The presence of H pylori infection does not directly affect the GB function.
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Aguirre AL, Center SA, Randolph JF, Yeager AE, Keegan AM, Harvey HJ, Erb HN. Gallbladder disease in Shetland Sheepdogs: 38 cases (1995-2005). J Am Vet Med Assoc 2007; 231:79-88. [PMID: 17605668 DOI: 10.2460/javma.231.1.79] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To determine risk, clinical features, and treatment responses for gallbladder disorders in Shetland Sheepdogs. DESIGN Retrospective case-control study. ANIMALS 38 Shetland Sheepdogs with gallbladder disease. PROCEDURES Medical records were reviewed for signalment, history, physical findings, laboratory results, imaging features, coexistent illnesses, histologic findings, treatments, and survival rates. RESULTS Mature dogs with gastrointestinal signs were predisposed (odds ratio, 7.2) to gallbladder disorders. Gallbladder mucocele was confirmed in 25 dogs. Concurrent problems included pancreatitis, hyperlipidemia, corticosteroid excess, hypothyroidism, protein-losing nephropathy, diabetes mellitus, cholelithiasis, and gallbladder dysmotility. Mortality rate was 68% with and 32% without bile peritonitis. Nonsurvivors had high WBC and neutrophil count and low potassium concentration. Although preprandial hypercholesterolemia, hypertriglyceridemia, and high serum liver enzyme activities were common, gallbladder disease was serendipitously discovered in 11 of 38 dogs. Histologic examination (n=20 dogs) revealed gallbladder cystic mucosal hyperplasia in 20 dogs, cholecystitis in 16, periportal hepatitis in 9, and vacuolar hepatopathy in 7. Surgery included cholecystectomy (n=17) and cholecystoenterostomy (4). In 1 hyperlipidemic dog without clinical signs, gallbladder mucocele resolved 6 months after beginning use of a fat-restricted diet and ursodeoxycholic acid. CONCLUSIONS AND CLINICAL RELEVANCE Shetland Sheepdogs are predisposed to gallbladder disorders, with mucoceles and concurrent dyslipidemia or dysmotility in many affected dogs. Most dogs were without clinical signs during mucocele development. Low survival rate after cholecystectomy in clinically affected dogs suggested that preemptive surgical interventions may be a more appropriate treatment strategy.
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Affiliation(s)
- Ale L Aguirre
- Departments of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
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Kim I, Ahn SH, Inagaki T, Choi M, Ito S, Guo GL, Kliewer SA, Gonzalez FJ. Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine. J Lipid Res 2007; 48:2664-72. [PMID: 17720959 DOI: 10.1194/jlr.m700330-jlr200] [Citation(s) in RCA: 461] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Bile acid concentrations are controlled by a feedback regulatory pathway whereby activation of the farnesoid X receptor (FXR) represses transcription of both the CYP7A1 gene, encoding the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, required for synthesis of cholic acid. The tissue-specific roles of FXR were examined using liver- and intestine-specific FXR-null models. FXR deficiency in either liver (Fxr DeltaL) or intestine (Fxr DeltaIE) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in Fxr DeltaL mice but not Fxr DeltaIE mice, demonstrating that activation of FXR in intestine but not liver is required for short-term repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone FGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, recombinant FGF15 repressed CYP7A1 mRNA levels without affecting CYP8B1 expression. These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1.
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Affiliation(s)
- Insook Kim
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Bergman E, Forsell P, Tevell A, Persson EM, Hedeland M, Bondesson U, Knutson L, Lennernäs H. Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase. Eur J Pharm Sci 2006; 29:205-14. [PMID: 16806856 DOI: 10.1016/j.ejps.2006.04.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2006] [Accepted: 04/25/2006] [Indexed: 10/24/2022]
Abstract
AIM The aim of this study was to investigate the biliary secretion of rosuvastatin in healthy volunteers using an intestinal perfusion method after administration of 10mg rosuvastatin dispersion in the intestine. METHODS The Loc-I-Gut tube was positioned in the distal duodenum/proximal jejunum and a semi-open segment was created by inflating the proximal balloon in ten volunteers. A dispersion of 10mg rosuvastatin was administered below the inflated balloon and bile was collected proximally of the inflated balloon. Bile and plasma samples were withdrawn every 20 min during a 4h period (absorption phase) and additional plasma samples were collected 24 and 48 h post-dose. RESULTS The study showed that there is a substantial and immediate transport of rosuvastatin into the human bile, with the maximum concentration appearing 42 min after dosing, 39,000+/-31,000 ng/ml. Approximately 11% of the administered intestinal dose was recovered in the bile after 240 min. At all time points the biliary concentration exceeded the plasma concentration, and the average bile to plasma ratio was 5200+/-9200 (range 89-33,900, median 2000). We were unable to identify any bile-specific metabolites of rosuvastatin in the present study. CONCLUSION Rosuvastatin is excreted via the biliary route in humans, and the transport and accumulation of rosuvastatin in bile compared to that in plasma is rapid and extensive. This intestinal perfusion technique offers a successful way to estimate the biliary secretion for drugs, metabolites and endogenous substances during the absorption phase in healthy volunteers.
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Affiliation(s)
- Ebba Bergman
- Department of Pharmacy, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden
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Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom SR, Suino-Powell K, Xu HE, Richardson JA, Gerard RD, Mangelsdorf DJ, Kliewer SA. Identification of a hormonal basis for gallbladder filling. Nat Med 2006; 12:1253-5. [PMID: 17072310 DOI: 10.1038/nm1501] [Citation(s) in RCA: 230] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2006] [Accepted: 10/03/2006] [Indexed: 01/24/2023]
Abstract
The cycle of gallbladder filling and emptying controls the flow of bile into the intestine for digestion. Here we show that fibroblast growth factor-15, a hormone made by the distal small intestine in response to bile acids, is required for gallbladder filling. These studies demonstrate that gallbladder filling is actively regulated by an endocrine pathway and suggest a postprandial timing mechanism that controls gallbladder motility.
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Affiliation(s)
- Mihwa Choi
- Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA
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Degirmenci B, Albayrak R, Haktanir A, Acar M, Yucel A. Acute effect of smoking on gallbladder emptying and refilling in chronic smokers and nonsmokers: A sonographic study. World J Gastroenterol 2006; 12:5540-3. [PMID: 17006996 PMCID: PMC4088241 DOI: 10.3748/wjg.v12.i34.5540] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To ultrasonographicaly evaluate the acute effects of smoking on gallbladder contraction and refilling in chronic smokers and nonsmokers.
METHODS: Fifteen chronic smokers (21-30 years old) and fifteen nonsmokers (21-35 years old) participated in this study. Chronic smokers were selected among the volunteers who had been smoking for at least 5 years and 10 cigarettes per day (mean 17.5/d). Examinations were performed in two separate days. In the first day, basal gallbladder (GB) volumes of volunteers were measured after 8-h fasting. After the examinations, participants had a meal containing at least 30-40 gram fat. Gallbladder volume was assessed at 5, 15, 30, 60, 120 and 180 min after the meal. In the second day, participants smoked 2 cigarettes after 8-h fasting. Then, they had the same meal, and gallbladder measurements were repeated at the same time points. Same procedures were applied to both groups.
RESULTS: The mean starving GB volumes were 23.3 ± 3.3 mL in the first day, 21.9 ± 3.0 mL in the second day in nonsmoker group and 18.3 ± 3.0 mL in the first day, 19.5 ± 2.8 mL in second day in smoker group. There was no significant difference between starving GB volumes. We did not find any significant difference between the GB volumes measured at 5, 15, 30, 60, 120 and 180 min in the first and second days in nonsmoker group. In smokers, post cigarette GB volume was found significantly higher at 5, 15 and 30 min which corresponded to GB contraction phase (P < 0.05). Control GB volume measurements were not significantly different between the two groups. Post-smoking GB volumes were also not significantly different between the two groups.
CONCLUSION: Smoking prolongs the maximal GB emptying time both in smokers and in nonsmokers though it is not significant. It delays GB contraction in chronic smokers and causes a significant decrease in GB emptying volume. Smoking causes no significant delay in GB refilling in both smokers and nonsmokers. These effects of smoking observed in acute phase result in bile stasis in GB. Bile stasis is the underlying cause of most GB disorders in chronic process.
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Affiliation(s)
- Bumin Degirmenci
- Department of Radiology, Faculty of Medicine, Kocatepe University, Afyon, Turkey.
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Büyükafşar K, Akça T, Nalan Tiftik R, Sahan-Firat S, Aydin S. Contribution of Rho-kinase in human gallbladder contractions. Eur J Pharmacol 2006; 540:162-7. [PMID: 16730697 DOI: 10.1016/j.ejphar.2006.04.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2006] [Revised: 04/11/2006] [Accepted: 04/25/2006] [Indexed: 01/19/2023]
Abstract
Rho/Rho-kinase-mediated pathway has been involved in a variety of physiological processes, including Ca2+ sensitization, which enhances smooth muscle contraction. In this study, first of all we investigated the expression of Rho-kinase (ROCK-2) and then the role of this protein in the control of smooth muscle contraction in the isolated human gallbladder. For this purpose, we examined the effects of a selective Rho-kinase inhibitor, (+)- (R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632, 10(-8)-3x10(-5) M) on carbachol (10(-8)-10(-4) M), cholecystokinin-8 (10(-8) M), endothelin-1 (10(-8) M), histamine (10(-5) M), neurokinin A (10(-7)-10(-6) M), 5-hydroxytryptamine (10(-6)-10(-5) M) and potassium chloride (KCl, 25-50 mM)-induced contractions as well as spontaneous contractile activity. Y-27632 (10(-5) M) significantly reduced 5-hydroxytryptamine, neurokinin A and KCl-induced contractions. Moreover, this Rho-kinase inhibitor (10(-8)-3x10(-5) M, cumulatively) relaxed the contractions produced by cholecystokinin-8, endothelin-1 and histamine in a concentration-dependent manner, being the pEC50 values for Y-27632 5.74+/-0.12, 5.33+/-0.09 and 5.95+/-0.18, respectively. Carbachol (10(-8)-10(-4) M) produced concentration-dependent contractions, which were also inhibited significantly by Y-27632. In addition, the spontaneous contractile activity was suppressed in the presence of Y-27632 (10(-6)-10(-5) M). Moreover, Western blot analysis has revealed that Rho-kinase is expressed in homogenates of the human gallbladder. Taken together, these results show that Rho-kinase is expressed in the human gallbladder, and it has an essential role in agonists and depolarization-induced contractions as well as spontaneous contractile activity.
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Affiliation(s)
- Kansu Büyükafşar
- Department of Pharmacology, Medical Faculty, Mersin University, Campus Yenişehir 33169 Mersin, Turkey.
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Degirmenci B, Acar M, Albayrak R, Yucel A, Haktanir A, Demirel R, Ellidokuz E. Effect of Sildenafil Citrate on Postprandial Gallbladder Motility. South Med J 2006; 99:208-11. [PMID: 16553093 DOI: 10.1097/01.smj.0000203333.29270.54] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Sildenafil stimulates the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway through inhibition of type 5 phosphodiesterase. NO-cGMP pathway causes smooth muscle relaxation. The aim of this study is to evaluate the effects of sildenafil on gallbladder motility. METHODS Twenty healthy male volunteers (21-35 years old) participated in this randomized, double blind, crossover, and placebo-controlled study. Oral sildenafil (50 mg) or placebo was randomly dispensed to each volunteer on two consecutive days. After the sildenafil or placebo, a special meal with a high fat content was administered. Gallbladder volume was measured using sonography preprandially and at 5, 15, 30, 60, 120 and 180 minutes postprandially. RESULTS Sildenafil showed an inhibitory effect on gallbladder contraction in healthy volunteers that began at 30 minutes. Gallbladder volumes showed significant differences at 30 minutes following the test meal (approximately 50-60 min after the sildenafil intake), between placebo (15.4 +/- 5.1 mL) and the sildenafil groups (19.3 +/- 6.1 mL) (P < 0.05). In addition, gallbladder volume was significantly higher during the refilling phase in the sildenafil group (P < 0.05 at 180 min). Maximal contraction was achieved at 60 minutes in each group. CONCLUSIONS Sildenafil constituted a significant inhibitory effect on gallbladder discharge in healthy individuals when compared with placebo group. Because of this inhibitory effect, sildenafil consumption for long periods may potentiate risks of gallbladder disorders and gallstone formation resulting from disturbed gallbladder motility.
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Affiliation(s)
- Bumin Degirmenci
- Department of Radiology, Kocatepe University Faculty of Medicine, Afyon, Turkey.
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Persson EM, Nilsson RG, Hansson GI, Löfgren LJ, Libäck F, Knutson L, Abrahamsson B, Lennernäs H. A clinical single-pass perfusion investigation of the dynamic in vivo secretory response to a dietary meal in human proximal small intestine. Pharm Res 2006; 23:742-51. [PMID: 16482422 DOI: 10.1007/s11095-006-9607-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2005] [Accepted: 11/28/2005] [Indexed: 10/25/2022]
Abstract
PURPOSE To investigate the gastrointestinal secretory and enzymatic responses to a liquid meal during in vivo perfusion of the proximal human jejunum. METHODS Human intestinal fluid was collected from the proximal jejunum by single-pass in vivo perfusion (Loc-I-Gut). The fluid was quantitatively collected at 10-min intervals during 90 min while perfusing a nutritional drink at 2 mL/min. Quantification of lipids in the fluid leaving the segment was performed by using novel chromatographic methods. RESULTS The overall bile acid concentration varied between 0.5 and 8.6 mM with a peak level 40 min after the start of the liquid meal perfusion. The total concentration of phospholipids was between 0.1 and 3.9 mM and there was a rapid degradation of phosphatidylcholine to lysophosphatidylcholine. The tri-, di-, monoglycerides and free fatty acid levels increased sharply in the beginning and reached steady-state levels between 7 and 9.5 mM. CONCLUSIONS There is a rapid secretion of bile in response to food. Most of the dietary lipids are found in the form of their degradation products in vivo in human jejunum. This novel in vivo characterization, based on direct and high-recovery sampling of intestinal fluids, forms a basis for further development of improved in vitro drug dissolution test media.
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Affiliation(s)
- Eva M Persson
- Department of Pharmacy, Uppsala University, Box 580, S-751 23, Uppsala, Sweden
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Sahan-Firat S, Tiftik RN, Nacak M, Büyükafşar K. Rho kinase expression and its central role in ovine gallbladder contractions elicited by a variety of excitatory stimuli. Eur J Pharmacol 2005; 528:169-75. [PMID: 16324691 DOI: 10.1016/j.ejphar.2005.10.055] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2005] [Revised: 10/21/2005] [Accepted: 10/26/2005] [Indexed: 12/18/2022]
Abstract
Rho kinase has contractile activity, which induces Ca2+ sensitization in various cells. Several receptors are linked to the Rho/Rho-kinase pathway. Therefore, in this study we aimed to demonstrate the central importance of this novel pathway for diverse excitatory stimuli in the smooth muscle of the sheep gallbladder. Accordingly, the effects of a Rho kinase inhibitor, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632, 10(-8)-3 x 10(-5) M), were investigated on cholecystokinin-8 (CCK-8, 10(-8) M), endothelin-1 (10(-8) M), carbachol (10(-6)-10(-5) M), 5-hydroxytryptamine (5-HT, 10(-6)-10(-5) M), histamine (10(-6)-10(-5) M), phenylephrine (10(-5)-10(-4) M), neurokinin A (10(-7)-10(-6) M), electrical field stimulation (40 V, 0.5 ms, 2, 4, 8, 16, 32 Hz, 15 s, 3 min intervals) and potassium chloride (KCl, 25-50 mM)-induced contractions as well as spontaneous contractile activity. Electrical field stimulation evoked tetrodotoxin (3 x 10(-6) M)-sensitive reproducible contractions, which were inhibited by atropine (2 x 10(-6) M) and potentiated by eserine (5 x 10(-7) M). EFS-induced contraction was significantly inhibited by Y-27632 (10(-5) M). In addition, spontaneous contractile activity was suppressed in the presence of the compound (10(-6)-10(-5) M). This Rho kinase inhibitor also dramatically decreased the contractions elicited by 5-HT, neurokinin A and carbachol. KCl-induced contraction, which was not atropine-sensitive, was also conspicuously attenuated by Y-27632. Moreover, Y-27632 (10(-8)-3 x 10(-5) M) relaxed gallbladder strips that were contracted by histamine, endothelin-1, CCK-8 and phenylephrine in a concentration-dependent manner. pEC50 values for Y-27632 were 6.25+/-0.10, 5.79+/-0.12, 5.83+/-0.09 and 5.70+/-0.13 for the contraction elicited by histamine, CCK-8, endothelin-1 and phenylephrine, respectively. Furthermore, we also demonstrated Rho kinase protein expression (ROCK-1 and ROCK-2) by Western blot analysis. In conclusion, ROCK is expressed in the smooth muscle of the ovine gallbladder, and it has a central role in the contractile activity induced by diverse excitatory stimuli.
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Affiliation(s)
- Seyhan Sahan-Firat
- Department of Pharmacology Medical Faculty Mersin University Campus Yenişehir 33169 Mersin, Turkey
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Montet JC, Caroli-Bosc FX, Ferrari P, Piche T, Baize N, Anty R, Montet AM, Rampal P, Tran A. Gallbladder motility and gut hormone plasma levels in subjects with and without gallstones. ACTA ACUST UNITED AC 2005; 29:569-72. [PMID: 15980753 DOI: 10.1016/s0399-8320(05)82131-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Hormonal control of gallbladder motility is still unclear in patients with cholelithiasis. In a case-control study, we determined the characteristics of gallbladder emptying evaluated sonographically and the hormone levels of somatostatin, gastrin, and pancreatic polypeptide, before and after a fatty meal in 10 gallstone patients compared with 20 healthy subjects. Patients with lithiasis had a larger residual volume (median 12,0 ml vs 6,5 ml; P = 0.01) and a lower gallbladder ejection fraction (43% vs 70%, P = 0.02) than healthy subjects. During fasting, plasma pancreatic polypeptide concentrations were significantly higher in lithiasis patients (P < 0.03). In contrast, no differences between the two groups of patients were observed during the post prandial period. Somatostatin and gastrin plasma levels were similar in the two groups. Lastly, the serum bile salt levels were in the normal range and were not different between groups both during fasting and postprandial states. We conclude that large basal plasma concentrations of pancreatic polypeptide, a gut peptide inducing gallbladder relaxation, may constitute a factor facilitating lithogenesis.
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Luo YL, Zeng JW, Yu M, Wei YL, Qu SY, Li W, Zheng TZ. Effect of rhubarb on contractile response of gallbladder smooth muscle strips isolated from guinea pigs. World J Gastroenterol 2005; 11:863-6. [PMID: 15682482 PMCID: PMC4250598 DOI: 10.3748/wjg.v11.i6.863] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2004] [Revised: 07/07/2004] [Accepted: 07/15/2004] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of rhubarb on contractile response of isolated gallbladder muscle strips from guinea pigs and its mechanism. METHODS Guinea pigs were killed to remove the whole gallbladder. Two or three smooth muscle strips (8 mm x 3 mm) were cut along the longitudinal direction. The mucosa on each strip was carefully removed. Each longitudinal muscle strip was suspended in a tissue chamber containing 5 mL Krebs solution (37 degrees), bubbled continuously with 950 mL/L O(2) and 50 mL/L CO(2). The resting tension (g), mean contractile amplitude (mm), and contractile frequency (waves/min) were simultaneously recorded on recorders. After 2-h equilibration, rhubarb (10, 20, 70, 200, 700, 1,000 g/L) was added cumulatively to the tissue chamber in turns every 2 min to observe their effects on gallbladder. Antagonists were given 3 min before administration of rhubarb to investigate the possible mechanism. RESULTS Rhubarb increased the resting tension (from 0 to 0.40+/-0.02, P<0.001), and decreased the mean contractile amplitude (from 5.22+/-0.71 to 2.73+/-0.41, P<0.001). It also increased the contractile frequency of the gallbladder muscle strips in guinea pigs (from 4.09+/-0.46 to 6.08+/-0.35, P<0.001). The stimulation of rhubarb on the resting tension decreased from 3.98+/-0.22 to 1.58+/-0.12 by atropine (P<0.001), from 3.98+/-0.22 to 2.09+/-0.19 by verapamil (P<0.001) and from 3.98+/-0.22 to 2.67+/-0.43 by phentolamine (P<0.005). But the effect was not inhibited by hexamethonium (P>0.05). In addition, the action of mean amplitude and frequency was not inhibited by the above antagonists. CONCLUSION Rhubarb can stimulate the motility of isolated gallbladder muscle strips from guinea pigs. The stimulation of rhubarb might be relevant with M receptor, Ca(2+) channel and alpha receptor partly.
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Affiliation(s)
- Ya-Li Luo
- Department of Physiology, Lanzhou Medical College, Lanzhou 730000, Gansu Province, China
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Moon SJ, An JM, Kim J, Lee SI, Ahn W, Kim KH, Seo JT. Pharmacological characterization of rebamipide: its cholecystokinin CCK1 receptor binding profile and effects on Ca2+ mobilization and amylase release in rat pancreatic acinar cells. Eur J Pharmacol 2004; 505:61-6. [PMID: 15556137 DOI: 10.1016/j.ejphar.2004.10.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2004] [Accepted: 10/12/2004] [Indexed: 11/17/2022]
Abstract
We previously reported that rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]-propionic acid) generated oscillations of intracellular Ca2+ concentration ([Ca2+]i) probably through the activation of cholecystokinin type 1 (CCK1) receptors in rat pancreatic acinar cells. Therefore, in the present study, we aimed to establish the pharmacological characteristics of rebamipide in rat pancreatic acinar cells. CCK-8S and rebamipide inhibited [125I]BH-CCK-8S binding to rat pancreatic acinar cell membranes with IC50 values of 3.13 nM and 37.7 microM, respectively. CCK-8S usually evoked [Ca2+]i oscillations at concentrations lower than 50 pM, and it induced biphasic [Ca2+]i increases at higher concentrations. In contrast to CCK-8S, rebamipide only induced [Ca2+]i oscillations at all the concentrations we used in this study. In addition, rebamipide was shown to inhibit high concentrations of CCK-8S-induced biphasic increases in [Ca2+]i, suggesting that rebamipide might be a partial agonist at cholecystokinin CCK1 receptors. Although rebamipide induced [Ca2+]i oscillations by activating the cholecystokinin CCK1 receptors, rebamipide did not cause amylase release and only inhibited CCK-stimulated amylase release reversibly and dose-dependently. However, rebamipide did not inhibit carbachol-, vasoactive intestinal polypeptide (VIP)-, and forskolin-induced amylase releases. These data indicate that rebamipide functions as a partial agonist for Ca2+ -mobilizing action, and it is also an antagonist for the amylase-releasing action of CCK.
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Affiliation(s)
- Seok Jun Moon
- Department of Oral Biology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea
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Kamerling IMC, Van Haarst AD, De Kam ML, Cohen AF, Masclee AAM, Burggraaf J. Gallbladder volume as a biomarker for the motilin effect in healthy volunteers and patients with functional dyspepsia. Aliment Pharmacol Ther 2004; 19:797-804. [PMID: 15043521 DOI: 10.1111/j.1365-2036.2004.01905.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIM To investigate a motilin effect on gallbladder volume in healthy volunteers and patients with functional dyspepsia. METHODS Forty-three healthy volunteers and 10 patients with functional dyspepsia received motilin (4 pmol.min/kg) or placebo in four separate double-blind, randomized, placebo-controlled, cross-over studies. The gallbladder volume was measured by ultrasonography. Analysis of variance of the combined data of these studies was performed to investigate a motilin effect on gallbladder volume and potential differences between patients and healthy volunteers. RESULTS The baseline gallbladder volume was similar for placebo and motilin treatment, as well as for patients and healthy volunteers. Motilin, compared with placebo, significantly decreased the gallbladder volume in healthy volunteers (P = 0.003) and patients (P < 0.0001). A linear concentration-response relationship was observed. The decrease in gallbladder volume by motilin was greater in patients (P = 0.03). The motilin effect was consistent between studies. CONCLUSION The interdigestive gallbladder volume is a non-invasive end-point for motilin activity, displaying a consistent response across studies, a clear response to motilin and a clear concentration-response relationship. However, it is less suitable as a biomarker for future pharmacological studies on motilin agonists or antagonists as the effect is probably indirect, and a relatively large study population of 27 subjects is required to demonstrate a 15% decrease in gallbladder volume. Further investigation is required to confirm altered gallbladder motility as a feature of functional dyspepsia.
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Malesci A, Pezzilli R, D'Amato M, Rovati L. CCK-1 receptor blockade for treatment of biliary colic: a pilot study. Aliment Pharmacol Ther 2003; 18:333-7. [PMID: 12895218 DOI: 10.1046/j.1365-2036.2003.01688.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Loxiglumide is a potent and selective cholecystokinin-1 (CCK-1) receptor antagonist able to inhibit gall-bladder contraction. AIM To assess the effect of CCK-1 receptor blockade on the pain of patients with biliary colic. PATIENTS AND METHODS Fourteen patients with biliary colic but no suspicion for acute cholecystitis, were randomly and blindly assigned to loxiglumide (50 mg i.v.) or hyoscine-N-butyl bromide (20 mg i.v.) treatment. Pain intensity was monitored by a Visual Analogue Scale. Patients with less than 80% response at 30 min, were retreated with a second injection of the same compound. RESULTS Reduction in pain score (mean +/- S.E.M.) was faster and significantly greater in patients treated with loxiglumide (n = 7) than in controls (n = 7): 88 +/- 7% vs. 47 +/- 12% after 20 min, P < 0.05; 92 +/- 6% vs. 49 +/- 13%, after 30 min, P < 0.05. Only one of seven patients treated with loxiglumide needed a second injection at 30 min (vs. six of seven controls, P < 0.05). No adverse effect was observed after either treatment. CONCLUSIONS Loxiglumide is highly effective in obtaining pain relief in patients with biliary colic. The analgesic effect of CCK-1 receptor blockade is superior to that of a conventional anticholinergic treatment.
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Affiliation(s)
- A Malesci
- Department of Internal Medicine, University of Milan, Milano, Italy.
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Trevisani M, Amadesi S, Schmidlin F, Poblete MT, Bardella E, Maggiore B, Harrison S, Figueroa CD, Tognetto M, Navarra G, Turini A, Bunnett NW, Geppetti P, De Giorgio R. Bradykinin B2 receptors mediate contraction in the normal and inflamed human gallbladder in vitro. Gastroenterology 2003; 125:126-35. [PMID: 12851878 DOI: 10.1016/s0016-5085(03)00694-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The components of the kinin system, including kinongens, kininogenases, and B(2) and B(1) receptors, are expressed and activated during inflammation. Here, we investigated the expression of the kinin B(2) receptor messenger RNA, kininogen and kallikrein immunoreactivity, and the ability of kinins to contract control and inflamed gallbladders in vitro. METHODS Human gallbladders, obtained from patients undergoing cholecystectomy either for acute cholecystitis secondary to gallstone disease or during elective gastro-entero-pancreatic surgery (controls), were processed for reverse-transcription polymerase chain reaction analysis, kallikrein and kininogen immunohistochemistry, binding studies, and in vitro contractility studies. RESULTS Tissue expression of B(2) receptor messenger RNA and specific binding of [(3)H]-bradykinin increased significantly in acute cholecystitis compared to controls. Kallikrein immunoreactivity was detected in the epithelium and infiltrating leukocytes, whereas kininogen immunoreactivity in the lumen of blood vessels and interstitial space. Bradykinin contracted isolated strips of control and acute cholecystitis gallbladders. In acute cholecystitis tissue, efficacy of bradykinin was higher than that of control gallbladders and similar to that of cholecystokinin. The contraction induced by bradykinin was significantly attenuated by B(2) receptor antagonism but not by cyclooxygenase inhibition and B(1), muscarinic, or tachykinin receptor antagonism. CONCLUSIONS All the components of the kinin system are expressed in the human gallbladder. Bradykinin is a powerful spasmogen via B(2) receptor activation in the normal and, especially, in the inflamed human gallbladder.
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Affiliation(s)
- Marcello Trevisani
- Department of Experimental Medicine and Clinical Medicine, Pharmacology Unit, University of Ferrara, Italy
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Abstract
Emptying the gallbladder is part of the complex process of food digestion. The gallbladder interacts with other gastrointestinal organs and its movements are coordinated and modified by functions of the stomach, intestine and pancreas. Many factors can modify gallbladder motility, for example, sex and age of the subject, their body mass, the kinds of food ingested and stimulus used. The assumption that the gallbladder progressively empties during meals and refills during fasting is incorrect. Using a combination of ultrasonography and cholescintigraphy, it is possible to measure absolute and net gallbladder emptying. In this way we demonstrated that the gallbladder begins to refill immediately after emptying begins, and the difference between net and absolute emptying of the gallbladder indicates the refilling of bile and provides a measure of bile turnover rate, an accurate index to assess gallbladder motility.
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Affiliation(s)
- N Prandini
- Nuclear Medicine Department, Azienda Ospedaliera-Universitaria, Corso Giovecca 203, Ferrara 44100, Italy.
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