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Bosch R, Petrone M, Arends R, Vicini P, Sijbrands EJG, Hoefman S, Snelder N. Characterisation of cotadutide's dual GLP-1/glucagon receptor agonistic effects on glycaemic control using an in vivo human glucose regulation quantitative systems pharmacology model. Br J Pharmacol 2024; 181:1874-1885. [PMID: 38403793 DOI: 10.1111/bph.16336] [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: 03/21/2023] [Revised: 10/06/2023] [Accepted: 01/18/2024] [Indexed: 02/27/2024] Open
Abstract
BACKGROUND AND PURPOSE Cotadutide is a dual GLP-1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP-1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585). EXPERIMENTAL APPROACH The cotadutide PK-4GI systems model was calibrated to clinical data by re-estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP-1 and glucagon receptor agonistic effects on glucose. KEY RESULTS Cotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP-1 receptor-mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200-μg cotadutide dose. CONCLUSION AND IMPLICATIONS The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP-1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds.
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Affiliation(s)
| | - Marcella Petrone
- Clinical Pharmacology, Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Rosalin Arends
- Clinical Pharmacology, Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Paolo Vicini
- Clinical Pharmacology, Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Eric J G Sijbrands
- Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
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2
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Bertoli D, Mark EB, Liao D, Brock C, Brock B, Knop FK, Krogh K, Frøkjær JB, Drewes AM. Pan-alimentary assessment of motility, luminal content, and structures: an MRI-based framework. Scand J Gastroenterol 2023; 58:1378-1390. [PMID: 37431198 DOI: 10.1080/00365521.2023.2233036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/01/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND Gastrointestinal symptoms originating from different segments overlap and complicate diagnosis and treatment. In this study, we aimed to develop and test a pan-alimentary framework for the evaluation of gastrointestinal (GI) motility and different static endpoints based on magnetic resonance imaging (MRI) without contrast agents or bowel preparation. METHODS Twenty healthy volunteers (55.6 ± 10.9 years, BMI 30.8 ± 9.2 kg/m2) underwent baseline and post-meal MRI scans at multiple time points. From the scans, the following were obtained: Gastric segmental volumes and motility, emptying half time (T50), small bowel volume and motility, colonic segmental volumes, and fecal water content. Questionnaires to assess GI symptoms were collected between and after MRI scans. KEY RESULTS We observed an increase in stomach and small bowel volume immediately after meal intake from baseline values (p<.001 for the stomach and p=.05 for the small bowel). The volume increase of the stomach primarily involved the fundus (p<.001) in the earliest phase of digestion with a T50 of 92.1 ± 35.3 min. The intake of the meal immediately elicited a motility increase in the small bowel (p<.001). No differences in colonic fecal water content between baseline and 105 min were observed. CONCLUSION & INFERENCES We developed a framework for a pan-alimentary assessment of GI endpoints and observed how different dynamic and static physiological endpoints responded to meal intake. All endpoints aligned with the current literature for individual gut segments, showing that a comprehensive model may unravel complex and incoherent gastrointestinal symptoms in patients.
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Affiliation(s)
- Davide Bertoli
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Esben B Mark
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Donghua Liao
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
| | - Birgitte Brock
- Department of Clinical Research, Steno Diabetes Center Copenhagen (SDCC), Copenhagen, Denmark
| | - Filip K Knop
- Department of Clinical Research, Steno Diabetes Center Copenhagen (SDCC), Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Jens B Frøkjær
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Asbjorn M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
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Lema-Perez L, Herrón-Bedoya A, Paredes-Ángel V, Hernández-Arango A, Builes-Montaño CE, Alvarez H. Estimation of glucose rate of appearance in portal vein circulation using a phenomenological-based model. PLoS One 2023; 18:e0285849. [PMID: 37228105 DOI: 10.1371/journal.pone.0285849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 05/02/2023] [Indexed: 05/27/2023] Open
Abstract
The joint work of the stomach and the small intestine plays a fundamental role in human digestion. In the stomach, food is turned into a semi-fluid mixture that is slowly released into the small intestine, where most enzymatic reactions occur, and nutrients are absorbed as they become available. This whole process is closely related to glucose homeostasis, mainly because of the appearance of glucose in the portal system and the energetic expenditure of the process itself. The current phenomenological-based model describes such effects of the digestive process on blood glucose concentration. It considers enzymatic and mechanical transformations, energetic expenditure, and the impact of macro-nutrients, fiber, and water on overall digestion and glucose absorption. The model estimates the rate of glucose appearance in the portal vein and is intended to be further integrated into existing models for other human organs and used in model-based systems such as an artificial pancreas with automated insulin delivery.
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Affiliation(s)
- Laura Lema-Perez
- Artificial Pancreas Trondheim (APT), Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Alejandro Herrón-Bedoya
- Kalman research group, Facultad de Minas, Universidad Nacional de Colombia, Medellín, Colombia
| | - Valentina Paredes-Ángel
- Kalman research group, Facultad de Minas, Universidad Nacional de Colombia, Medellín, Colombia
| | - Andrea Hernández-Arango
- Kalman research group, Facultad de Minas, Universidad Nacional de Colombia, Medellín, Colombia
| | | | - Hernan Alvarez
- Kalman research group, Facultad de Minas, Universidad Nacional de Colombia, Medellín, Colombia
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4
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Digestion of meat proteins in a human-stomach: A CFD simulation study. INNOV FOOD SCI EMERG 2022. [DOI: 10.1016/j.ifset.2022.103252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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5
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Rochira I, Chanpong A, Biassoni L, Easty M, Morris E, Saliakellis E, Lindley K, Thapar N, Rybak A, Borrelli O. Transpyloric propagation and liquid gastric emptying in children with foregut dysmotility. Neurogastroenterol Motil 2022; 34:e14334. [PMID: 35254724 DOI: 10.1111/nmo.14334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 09/14/2021] [Accepted: 01/19/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND/OBJECTIVES Gastric emptying (GE) requires precise antropyloroduodenal coordination for effective transpyloric flow, the mechanisms of which are still unclear. We aimed to correlate gastric antral function assessed by antroduodenal manometry (ADM) with GE scintigraphy (GES) for liquid feeds in children with suspected gastrointestinal dysmotility. METHODS Children who underwent both ADM and GES over a five-year period were reviewed. ADM tracings were re-analyzed to assess antral frequency, amplitude, and motility index (MI) pre-prandially and postprandially. Transpyloric propagation (TPP) was defined as antegrade propagated antral activity preceding duodenal phase III of the migrating motor complex (MMC). TPP was defined as "poor" if occurring in <50% of all presented duodenal phases III. For GES, regions of interest over the whole stomach, fundus, and antrum were drawn to calculate GE half-time (GE-T1/2 ) and retention rate (RR) in each region at 1 and 2 h. RESULTS Forty-seven children (median age: 7.0 years) were included. Twenty-two had PIPO, 14 functional GI disorders, and 11 gastroparesis. Children with poor TPP had longer GE-T1/2 (113.0 vs 66.5 min, p = 0.028), higher RR of the whole stomach and fundus at 1 h (79.5% vs 63.5%, p = 0.038; 60.0% vs 41.0%, p = 0.022, respectively) and 2 h (51.0% vs 10.5%, p = 0.005; 36.0% vs 6.5%, p = 0.004, respectively). The pre-prandial antral amplitude of contractions inversely correlated with GE-T1/2 , RR of the whole stomach, and fundus at 2 h. CONCLUSIONS TPP during phase III of the MMC correlated with gastric emptying of liquid and its assessment on ADM might predict abnormalities in postprandial gastric function.
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Affiliation(s)
- Ilaria Rochira
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK.,Department of Paediatrics, Children's Hospital, ASST Spedali Civili, University of Brescia, Brescia, Italy
| | - Atchariya Chanpong
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK.,Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.,Stem cell and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Lorenzo Biassoni
- Nuclear Medicine Unit, Department of Radiology, Great Ormond Street Hospital for Children, London, UK
| | - Marina Easty
- Nuclear Medicine Unit, Department of Radiology, Great Ormond Street Hospital for Children, London, UK
| | - Elizabeth Morris
- Nuclear Medicine Unit, Department of Radiology, Great Ormond Street Hospital for Children, London, UK.,Nuclear Medicine Physics, Clinical Physics, Barts Health NHS Trust, London, UK
| | - Efstratios Saliakellis
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
| | - Keith Lindley
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
| | - Nikhil Thapar
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK.,Stem cell and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK.,Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Queensland, Australia
| | - Anna Rybak
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
| | - Osvaldo Borrelli
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
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Anand O, Pepin XJH, Kolhatkar V, Seo P. The Use of Physiologically Based Pharmacokinetic Analyses-in Biopharmaceutics Applications -Regulatory and Industry Perspectives. Pharm Res 2022; 39:1681-1700. [PMID: 35585448 DOI: 10.1007/s11095-022-03280-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/27/2022] [Indexed: 12/18/2022]
Abstract
The use of physiologically based pharmacokinetic (PBPK) modeling to support the drug product quality attributes, also known as physiologically based biopharmaceutics modeling (PBBM) is an evolving field and the interest in using PBBM is increasing. The US-FDA has emphasized on the use of patient centric quality standards and clinically relevant drug product specifications over the years. Establishing an in vitro in vivo link is an important step towards achieving the goal of patient centric quality standard. Such a link can aid in constructing a bioequivalence safe space and establishing clinically relevant drug product specifications. PBBM is an important tool to construct a safe space which can be used during the drug product development and lifecycle management. There are several advantages of using the PBBM approach, though there are also a few challenges, both with in vitro methods and in vivo understanding of drug absorption and disposition, that preclude using this approach and therefore further improvements are needed. In this review we have provided an overview of experience gained so far and the current perspective from regulatory and industry point of view. Collaboration between scientists from regulatory, industry and academic fields can further help to advance this field and deliver on promises that PBBM can offer towards establishing patient centric quality standards.
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Affiliation(s)
- Om Anand
- Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, Maryland, USA.
| | - Xavier J H Pepin
- New Modalities and Parenteral Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK
| | - Vidula Kolhatkar
- Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, Maryland, USA
| | - Paul Seo
- Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, Maryland, USA
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7
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Gardner-Russell J, Kuriakose J, Hao MM, Stamp LA. Upper Gastrointestinal Motility, Disease and Potential of Stem Cell Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:319-328. [PMID: 36587169 DOI: 10.1007/978-3-031-05843-1_29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Many gastrointestinal motility disorders arise due to defects in the enteric nervous system. Achalasia and gastroparesis are two extremely debilitating digestive diseases of the upper gastrointestinal tract caused in part by damage or loss of the nitrergic neurons in the esophagus and stomach. Most current pharmacological and surgical interventions provide no long-term relief from symptoms, and none address the cause. Stem cell therapy, to replace the missing neurons and restore normal gut motility, is an attractive alternative therapy. However, there are a number of hurdles that must be overcome to bring this exciting research from the bench to the bedside.
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Affiliation(s)
- Jesse Gardner-Russell
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC, Australia
| | - Jakob Kuriakose
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC, Australia
| | - Marlene M Hao
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC, Australia
| | - Lincon A Stamp
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC, Australia.
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8
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Size and Number of Food Boluses in the Stomach after Eating Different Meals: Magnetic Resonance Imaging Insights in Healthy Humans. Nutrients 2021; 13:nu13103626. [PMID: 34684627 PMCID: PMC8539055 DOI: 10.3390/nu13103626] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 10/12/2021] [Indexed: 11/20/2022] Open
Abstract
Oral processing of food results in the formation of food boluses, which are then swallowed and reach the stomach for further digestion. The number, size and surface properties of the boluses will affect their processing and emptying from the stomach. Knowledge of these parameters, however, is incomplete due to limitations of the techniques used. In this work, non-invasive magnetic resonance imaging (MRI) was used for the first time to measure boluses in the stomach a few minutes after swallowing. Three groups of nine healthy participants were fed three different meals: chicken and roasted vegetables (Meal 1), bread and jam (Meal 2) and cheese and yogurt (Meal 3), and then, their stomach content was imaged. The median number of boluses within the stomach was 282, 106 and 9 for Meal 1, Meal 2 and Meal 3 (p < 0.0001) with an average volume of 0.47 mL, 2.4 mL and 13.6 mL, respectively (p < 0.0001). The cohesiveness as well as the meal composition seem to play a key role in the resulting boluses. These new in vivo data from undisturbed organ imaging can improve knowledge of the digestion process, which will, in turn, inform in vitro and in silico modelling of digestion, thus improving their in vitro/in vivo relevance.
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9
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Wagner C, Kesisoglou F, Pepin XJH, Parrott N, Emami Riedmaier A. Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models. AAPS JOURNAL 2021; 23:85. [PMID: 34142242 DOI: 10.1208/s12248-021-00601-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/20/2021] [Indexed: 11/30/2022]
Abstract
Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.
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Affiliation(s)
- Christian Wagner
- Pharmaceutical Technologies, Chemical and Pharmaceutical Development, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
| | | | - Xavier J H Pepin
- New Modalities and Parenteral Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK
| | - Neil Parrott
- Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Basel, Switzerland
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10
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Pepin XJH, Huckle JE, Alluri RV, Basu S, Dodd S, Parrott N, Emami Riedmaier A. Understanding Mechanisms of Food Effect and Developing Reliable PBPK Models Using a Middle-out Approach. AAPS JOURNAL 2021; 23:12. [PMID: 33398593 DOI: 10.1208/s12248-020-00548-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/07/2020] [Indexed: 12/14/2022]
Abstract
Over the last 10 years, 40% of approved oral drugs exhibited a significant effect of food on their pharmacokinetics (PK) and currently the only method to characterize the effect of food on drug absorption, which is recognized by the authorities, is to conduct a clinical evaluation. Within the pharmaceutical industry, there is a significant effort to predict the mechanism and clinical relevance of a food effect. Physiologically based pharmacokinetic (PBPK) models combining both drug-specific and physiology-specific data have been used to predict the effect of food on absorption and to reveal the underlying mechanisms. This manuscript provides detailed descriptions of how a middle-out modeling approach, combining bottom-up in vitro-based predictions with limited top-down fitting of key model parameters for clinical data, can be successfully used to predict the magnitude and direction of food effect when it is predicted poorly by a bottom-up approach. For nefazodone, a mechanistic clearance for the gut and liver was added, for furosemide, an absorption window was introduced, and for aprepitant, the biorelevant solubility was refined using multiple solubility measurements. In all cases, these adjustments were supported by literature data and showcased a rational approach to assess the factors limiting absorption and exposure.
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Affiliation(s)
- Xavier J H Pepin
- New Modalities and Parenteral Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK.
| | - James E Huckle
- Drug Product Technology, Amgen, Thousand Oaks, California, USA
| | - Ravindra V Alluri
- Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Sumit Basu
- Pharmacokinetic, Pharmacodynamic and Drug Metabolism-Quantitative Pharmacology and Pharmacometrics (PPDM-QP2), Merck & Co., Inc., West Point, Pennsylvania, USA
| | - Stephanie Dodd
- Chemical & Pharmaceutical Profiling, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA
| | - Neil Parrott
- Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Basel, Switzerland
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Limketkai BN, LeBrett W, Lin L, Shah ND. Nutritional approaches for gastroparesis. Lancet Gastroenterol Hepatol 2020; 5:1017-1026. [PMID: 33065041 DOI: 10.1016/s2468-1253(20)30078-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 12/12/2022]
Abstract
Patients with gastroparesis often have signs and symptoms including nausea, vomiting, epigastric discomfort, and early satiety, thus leading to inadequate food intake and a high risk of malnutrition. There is a considerable scarcity of data about nutritional strategies for gastroparesis, and current practices rely on extrapolated evidence. Some approaches include the modification of food composition, food consistency, and food volume in the context of delayed gastric emptying. If the patient is unable to consume adequate calories through a solid food diet, stepwise nutritional interventions could include the use of liquid meals, oral nutrition supplements, enteral nutrition, and parenteral nutrition. This Review discusses the role, rationale, and current evidence of diverse nutritional interventions in the management of gastroparesis.
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Affiliation(s)
- Berkeley N Limketkai
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, CA, USA.
| | - Wendi LeBrett
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, CA, USA
| | - Lisa Lin
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA School of Medicine, Los Angeles, CA, USA
| | - Neha D Shah
- Nutrition and Food Services, University of California San Francisco, San Francisco, CA, USA
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12
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Abstract
This review outlines the current use of magnetic resonance (MR) techniques to study digestion and highlights their potential for providing markers of digestive processes such as texture changes and nutrient breakdown. In vivo digestion research can be challenging due to practical constraints and biological complexity. Therefore, digestion is primarily studied using in vitro models. These would benefit from further in vivo validation. NMR is widely used to characterise food systems. MRI is a related technique that can be used to study both in vitro model systems and in vivo gastro-intestinal processes. MRI allows visualisation and quantification of gastric processes such as gastric emptying and coagulation. Both MRI and NMR scan sequences can be configured to be sensitive to different aspects of gastric or intestinal contents. For example, magnetisation transfer and chemical exchange saturation transfer can detect proton (1H) exchange between water and proteins. MRI techniques have the potential to provide molecular-level and quantitative information on in vivo gastric (protein) digestion. This requires careful validation in order to understand what these MR markers of digestion mean in a specific digestion context. Combined with other measures they can be used to validate and inform in vitro digestion models. This may bridge the gap between in vitro and in vivo digestion research and can aid the optimisation of food properties for different applications in health and disease.
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13
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Avvari RK. Theoretical modeling of the resistance to gastric emptying and duodenogastric reflux due to pyloric motility alone, presuming antral and duodenal quiescence. J Theor Biol 2020; 508:110460. [PMID: 32891592 DOI: 10.1016/j.jtbi.2020.110460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 08/02/2020] [Accepted: 08/20/2020] [Indexed: 01/08/2023]
Abstract
A theoretical model of the pyloric channel, approximated as a two-dimensional tube with sinusoidal corrugation, is developed to estimate the degree of resistance offered by the pylorus to transpyloric flow (gastric emptying and duodenogastric reflux) in the viscous regime. Study indicates that the resistance of the channel depends on pressure gradient, flow behavior index and channel diameter. Flow is majorly determined by the extent of luminal opening; since they scale to fourth power of the diameter for Newtonian flow, with the exponent being higher for pseudoplastic and lesser in case of dilatants relative to Newtonian fluid. At zero pressure difference, across the channel, the closing pylorus drives the aborad propulsion of the contents at the intestinal end, and at the gastric end the flow is driven along the orad direction. While no transfer of contents occur at the centre of pylorus due to zero pressure gradients, it is essential to have a non-zero pressure difference to drive the flow through the channel. The extent of pressure difference is found to linearly relate to the transpyloric flow rate. The resistive function of the pyloric channel is observed at a higher occlusion where there is a development of higher pressure barrier that is sensitive to the flow behavior index, frequency, occlusion, and contraction length.
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Affiliation(s)
- Ravi Kant Avvari
- Department of Biotechnology and Medical Engineering, NIT Rourkela, Odisha 769008, India.
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14
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Banerjee S, Pal A, Fox M. Volume and position change of the stomach during gastric accommodation and emptying: A detailed three-dimensional morphological analysis based on MRI. Neurogastroenterol Motil 2020; 32:e13865. [PMID: 32390262 DOI: 10.1111/nmo.13865] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 03/13/2020] [Accepted: 04/02/2020] [Indexed: 01/11/2023]
Abstract
BACKGROUND The proximal and distal regions of the stomach are thought to have different roles during gastric accommodation and emptying; however, regional changes in gastric structure and function during and after a meal have not been described in detail. This study applied non-invasive imaging to study changes in regional gastric volume and morphology during accommodation and emptying of a liquid nutrient meal. METHOD MRI studies were performed on 16 healthy volunteers. Three-dimensional (3D) gastric morphology was reconstructed by validated image processing technology. The 3D models were segmented into seven regions. The relative contribution of each region to gastric accommodation and emptying was assessed. Changes in morphology were documented by tracking movements of four distinct gastric landmarks. KEY RESULTS The initial 100 mL liquid nutrient increases distal stomach volume more than that of other gastric regions (∆V7 = 28 ± 6% ∆TGV; P ≤ .05). Subsequent volume is accommodated mainly in the proximal stomach (∆V1 = 42 ± 10% ∆TGV; P ≤ .05). Early-phase emptying occurs from distal stomach with proximal stomach volume remaining stable. Subsequently, distal stomach volume remains stable while proximal stomach volume decreases progressively. During gastric filling, the stomach elongates and expands anteriorly and inferiorly (15.2 ± 7.4 mm and 32.3 ± 8.4 mm, respectively, for the incisural midpoint) with torsion indicated by ~70° difference in the movements of proximal and distal gastric landmarks. CONCLUSIONS AND INFERENCES Non-invasive MRI describes volume change and distribution of a liquid meal within proximal and distal stomach during gastric accommodation and emptying. Additionally, novel observations of changes to 3D gastric morphology within the abdomen are documented.
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Affiliation(s)
- Sreerup Banerjee
- Department of Biological Sciences and Bio-Engineering (BSBE), Indian Institute of Technology Kanpur (IITK), Kanpur, India
| | - Anupam Pal
- Department of Biological Sciences and Bio-Engineering (BSBE), Indian Institute of Technology Kanpur (IITK), Kanpur, India
| | - Mark Fox
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Switzerland.,NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.,Digestive Function: Basel, Laboratory and Clinic for motility disorders and functional GI diseases, Center for integrative Gastroenterology, Klinik Arlesheim, Arlesheim, Switzerland
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15
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Natural Choline from Egg Yolk Phospholipids Is More Efficiently Absorbed Compared with Choline Bitartrate; Outcomes of A Randomized Trial in Healthy Adults. Nutrients 2019; 11:nu11112758. [PMID: 31766273 PMCID: PMC6893749 DOI: 10.3390/nu11112758] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/28/2019] [Accepted: 11/08/2019] [Indexed: 11/21/2022] Open
Abstract
Choline is a vitamin-like essential nutrient, important throughout one’s lifespan. Therefore, choline salts are added to infant formula, supplements and functional foods. However, if choline is present in a natural form, e.g. bound to phospholipids, it may be more efficiently absorbed. The study’s aim was to evaluate if choline uptake is improved after consumption of an egg yolk phospholipid drink, containing 3 g of phospholipid bound choline, compared to a control drink with 3 g of choline bitartrate. We performed a randomized, double blind, cross-over trial with 18 participants. Plasma choline, betaine and dimethylglycine concentrations were determined before and up to six hours after consumption of the drinks. The plasma choline response, as determined by the incremental area under the curve, was four times higher after consumption of the egg yolk phospholipid drink compared with the control drink (p < 0.01). Similar outcomes were also observed for choline’s main metabolites, betaine (p < 0.01) and dimethylglycine (p = 0.01). Consumption of natural choline from egg yolk phospholipids improved choline absorption compared to consumption of chemically produced choline bitartrate. This information is of relevance for the food industry, instead of adding choline-salts, adding choline from egg yolk phospholipids can improve choline uptake and positively impact health.
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Abstract
This review covers the epidemiology, pathophysiology, clinical features, diagnosis, and management of diabetic gastroparesis, and more broadly diabetic gastroenteropathy, which encompasses all the gastrointestinal manifestations of diabetes mellitus. Up to 50% of patients with type 1 and type 2 DM and suboptimal glycemic control have delayed gastric emptying (GE), which can be documented with scintigraphy, 13C breath tests, or a wireless motility capsule; the remainder have normal or rapid GE. Many patients with delayed GE are asymptomatic; others have dyspepsia (i.e., mild to moderate indigestion, with or without a mild delay in GE) or gastroparesis, which is a syndrome characterized by moderate to severe upper gastrointestinal symptoms and delayed GE that suggest, but are not accompanied by, gastric outlet obstruction. Gastroparesis can markedly impair quality of life, and up to 50% of patients have significant anxiety and/or depression. Often the distinction between dyspepsia and gastroparesis is based on clinical judgement rather than established criteria. Hyperglycemia, autonomic neuropathy, and enteric neuromuscular inflammation and injury are implicated in the pathogenesis of delayed GE. Alternatively, there are limited data to suggest that delayed GE may affect glycemic control. The management of diabetic gastroparesis is guided by the severity of symptoms, the magnitude of delayed GE, and the nutritional status. Initial options include dietary modifications, supplemental oral nutrition, and antiemetic and prokinetic medications. Patients with more severe symptoms may require a venting gastrostomy or jejunostomy and/or gastric electrical stimulation. Promising newer therapeutic approaches include ghrelin receptor agonists and selective 5-hydroxytryptamine receptor agonists.
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Affiliation(s)
- Adil E Bharucha
- Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Yogish C Kudva
- Division of Endocrinology. Mayo Clinic, Rochester, Minnesota
| | - David O Prichard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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17
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Haldar S, Gan L, Tay SL, Ponnalagu S, Henry CJ. Postprandial Glycemic and Insulinemic Effects of the Addition of Aqueous Extracts of Dried Corn Silk, Cumin Seed Powder or Tamarind Pulp, in Two Forms, Consumed with High Glycemic Index Rice. Foods 2019; 8:foods8100437. [PMID: 31554322 PMCID: PMC6835365 DOI: 10.3390/foods8100437] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/13/2019] [Accepted: 09/19/2019] [Indexed: 12/22/2022] Open
Abstract
Several plant-based traditional ingredients in Asia are anecdotally used for preventing and/or treating type 2 diabetes. We investigated three such widely consumed ingredients, namely corn silk (CS), cumin (CU), and tamarind (TA). The aim of the study was to determine the effects of aqueous extracts of these ingredients consumed either as a drink (D) with high-glycemic-index rice or added to the same amount of rice during cooking (R) on postprandial glycemia (PPG), insulinemia (PPI), and blood pressure (BP), over a 3 h measurement period. Eighteen healthy Chinese men (aged 37.5 ± 12.5 years, BMI 21.8 ± 1.67 kg/m2) took part in a randomized crossover trial, each completing up to nine sessions. Compared to the control meal (plain rice + plain water), the addition of test extracts in either form did not modulate PPG, PPI, or BP. However, the extracts when added within rice while cooking gave rise to significantly lower PPI than when consumed as a drink (p < 0.01). Therefore, the form of consumption of phytochemical-rich ingredients can differentially modulate glucose homeostasis. This study also highlights the need for undertaking randomized controlled clinical trials with traditional foods/components before claims are made on their specific health effects.
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Affiliation(s)
- Sumanto Haldar
- Clinical Nutrition Research Centre (CNRC), Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore 117609, Singapore.
| | - Linda Gan
- Clinical Nutrition Research Centre (CNRC), Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore 117609, Singapore.
| | - Shia Lyn Tay
- Clinical Nutrition Research Centre (CNRC), Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore 117609, Singapore.
| | - Shalini Ponnalagu
- Clinical Nutrition Research Centre (CNRC), Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore 117609, Singapore.
| | - Christiani Jeyakumar Henry
- Clinical Nutrition Research Centre (CNRC), Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), 30 Medical Drive, Singapore 117609, Singapore.
- Department of Biochemistry, National University of Singapore, Singapore 117596, Singapore.
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18
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Increasing intake of dietary soluble nutrients affects digesta passage rate in the stomach of growing pigs. Br J Nutr 2019; 121:529-537. [DOI: 10.1017/s0007114518003756] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
AbstractThe passage rate of solids and liquids through the gastrointestinal tract differs. Increased dietary nutrient solubility causes nutrients to shift from the solid to the liquid digesta fraction and potentially affect digesta passage kinetics. We quantified: (1) the effect of three levels of dietary nutrient solubility (8, 19 and 31 % of soluble protein and sucrose in the diet) at high feed intake level (S) and (2) the effect of lowv.high feed intake level (F), on digesta passage kinetics in forty male growing pigs. The mean retention time (MRT) of solids and liquids in the stomach and small intestine was assessed using TiO2and Cr-EDTA, respectively. In addition, physicochemical properties of digesta were evaluated. Overall, solids were retained longer than liquids in the stomach (2·0 h,P<0·0001) and stomach+small intestine (1·6 h,P<0·001). When S increased, MRT in stomach decreased by 1·3 h for solids (P=0·01) and 0·7 h for liquids (P=0·002) but only at the highest level of S. When F increased using low-soluble nutrients, MRT in stomach increased by 0·8 h for solids (P=0·041) and 0·7 h for liquids (P=0·0001). Dietary treatments did not affect water-binding capacity and viscosity of digesta. In the stomach of growing pigs, dietary nutrient solubility affects digesta MRT in a non-linear manner, while feed intake level increases digesta MRT depending on dietary nutrient solubility. Results can be used to improve predictions on the kinetics of nutrient passage and thereby of nutrient digestion and absorption in the gastrointestinal tract.
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19
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Evans GH, McLaughlin J, Yau AMW. The Effect of Glucose or Fructose Added to a Semi-solid Meal on Gastric Emptying Rate, Appetite, and Blood Biochemistry. Front Nutr 2018; 5:94. [PMID: 30364080 PMCID: PMC6191474 DOI: 10.3389/fnut.2018.00094] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 09/20/2018] [Indexed: 01/09/2023] Open
Abstract
The ingestion of fructose is of interest due to previously reported differences in gastrointestinal, appetite, and metabolic effects when compared to glucose ingestion when ingested in liquid solution. The aim of this study was to examine these variables when fructose and glucose are added to a semi-solid meal. Seven healthy male participants completed three experimental trials involving the ingestion of 300 mL of semi-skimmed milk mixed with 40 g of instant porridge mix (CON) and with the addition of either 40 g of glucose (GLU) or fructose (FRU). Subjective feelings of appetite were assessed for 2 h after ingestion with blood samples collected at regular intervals. Gastric emptying rate was assessed using the 13C breath test method. Half emptying time was not different between trials (CON = 159 ± 51 min; GLU = 197 ± 46 min; FRU = 198 ± 67 min: P = 0.117). No differences were observed for any subjective measurements of appetite (P > 0.05) while blood glucose was elevated (P < 0.05) 20 min after ingestion on both GLU and FRU with this tending to be higher on GLU than FRU. FRU resulted in greater (P < 0.05) blood lactate concentrations than on the other trials. The results of this study demonstrate that gastric emptying rate of glucose and fructose is similar when ingested in a semi-solid meal. In addition, there is little difference in appetite response between these sugars, however, there are some differences in metabolic response which deserve further study.
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Affiliation(s)
- Gethin H Evans
- School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom
| | - John McLaughlin
- Division of Diabetes, Endocrinology and Gastroenterology, School of Medical Sciences, University of Manchester and Salford Royal Hospitals, Manchester, United Kingdom
| | - Adora M W Yau
- School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom
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20
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Effects of Dissolution Medium pH and Simulated Gastrointestinal Contraction on Drug Release From Nifedipine Extended-Release Tablets. J Pharm Sci 2018; 108:1189-1194. [PMID: 30343136 DOI: 10.1016/j.xphs.2018.10.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 09/17/2018] [Accepted: 10/11/2018] [Indexed: 12/24/2022]
Abstract
In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products.
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21
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Wake-up Call to Clinicians: The Impact of Sleep Dysfunction on Gastrointestinal Health and Disease. J Clin Gastroenterol 2018; 52:194-203. [PMID: 29189428 DOI: 10.1097/mcg.0000000000000963] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Sleep dysfunction is an epidemic affecting a large portion of the adult population. Recent studies have linked sleep dysfunction with an upregulation of proinflammatory cytokines (eg, tumor necrosis factor-α, interleukin-1 and interleukin-6), the implications of which can have a profound impact on a variety of gastrointestinal disease. In particular, sleep dysfunction seems to accelerate disease states characterized by inflammation (eg, gastroesophageal reflux disease, irritable bowel syndrome and functional dyspepsia, chronic liver disease, inflammatory bowel disease, and colorectal cancer). This article evaluates the complex interplay between sleep dysfunction and gastrointestinal health and disease.
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22
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Moxon TE, Nimmegeers P, Telen D, Fryer PJ, Van Impe J, Bakalis S. Effect of chyme viscosity and nutrient feedback mechanism on gastric emptying. Chem Eng Sci 2017; 171:318-330. [PMID: 29104301 PMCID: PMC5569601 DOI: 10.1016/j.ces.2017.05.048] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric emptying rate linked to intestinal bioaccessability by feedback mechanism. Gastric secretion model links the secretion rate to the gastric viscosity. Model fits emptying of low and high viscosity liquid meals. A comprehensive mathematical model of the digestive processes in humans could allow for better design of functional foods which may play a role in stemming the prevalence of food related diseases around the world. This work presents a mathematical model for a nutrient based feedback mechanism controlling gastric emptying, which has been identified in vivo by numerous researchers. The model also takes into account the viscosity of nutrient meals upon gastric secretions and emptying. The results show that modelling the nutrient feedback mechanism as an on/off system, with an initial emptying rate dependent upon the secretion rate (which is a function of the gastric chyme viscosity) provides a good fit to the trends of emptying rate for liquid meals of low and high nutrient content with varying viscosity.
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Affiliation(s)
- Thomas E Moxon
- Department of Chemical Engineering, University of Birmingham, Edgbaston, UK
| | | | - Dries Telen
- Department of Chemical Engineering, BioTeC+ & OPTEC, KU Leuven, Belgium
| | - Peter J Fryer
- Department of Chemical Engineering, University of Birmingham, Edgbaston, UK
| | - Jan Van Impe
- Department of Chemical Engineering, BioTeC+ & OPTEC, KU Leuven, Belgium
| | - Serafim Bakalis
- Department of Chemical Engineering, University of Birmingham, Edgbaston, UK
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23
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Camps G, Mars M, de Graaf C, Smeets PA. A tale of gastric layering and sieving: Gastric emptying of a liquid meal with water blended in or consumed separately. Physiol Behav 2017; 176:26-30. [DOI: 10.1016/j.physbeh.2017.03.029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Revised: 03/17/2017] [Accepted: 03/17/2017] [Indexed: 10/19/2022]
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25
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Mansell EJ, Docherty PD, Chase JG. Shedding light on grey noise in diabetes modelling. Biomed Signal Process Control 2017. [DOI: 10.1016/j.bspc.2016.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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26
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Microencapsulated bitter compounds (from Gentiana lutea) reduce daily energy intakes in humans. Br J Nutr 2016; 116:1841-1850. [PMID: 27829482 DOI: 10.1017/s0007114516003858] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Mounting evidence showed that bitter-tasting compounds modulate eating behaviour through bitter taste receptors in the gastrointestinal tract. This study aimed at evaluating the influence of microencapsulated bitter compounds on human appetite and energy intakes. A microencapsulated bitter ingredient (EBI) with a core of bitter Gentiana lutea root extract and a coating of ethylcellulose-stearate was developed and included in a vanilla microencapsulated bitter ingredient-enriched pudding (EBIP). The coating masked bitterness in the mouth, allowing the release of bitter secoiridoids in the gastrointestinal tract. A cross-over randomised study was performed: twenty healthy subjects consumed at breakfast EBIP (providing 100 mg of secoiridoids) or the control pudding (CP) on two different occasions. Blood samples, glycaemia and appetite ratings were collected at baseline and 30, 60, 120 and 180 min after breakfast. Gastrointestinal peptides, endocannabinoids (EC) and N-acylethanolamines (NAE) were measured in plasma samples. Energy intakes were measured at an ad libitum lunch 3 h after breakfast and over the rest of the day (post lunch) through food diaries. No significant difference in postprandial plasma responses of gastrointestinal hormones, glucose, EC and NAE and of appetite between EBIP and CP was found. However, a trend for a higher response of glucagon-like peptide-1 after EBIP than after CP was observed. EBIP determined a significant 30 % lower energy intake over the post-lunch period compared with CP. These findings were consistent with the tailored release of bitter-tasting compounds from EBIP along the gastrointestinal tract. This study demonstrated that microencapsulated bitter secoiridoids were effective in reducing daily energy intake in humans.
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27
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Bornhorst GM, Drechsler KC, Montoya CA, Rutherfurd SM, Moughan PJ, Singh RP. Gastric protein hydrolysis of raw and roasted almonds in the growing pig. Food Chem 2016; 211:502-8. [DOI: 10.1016/j.foodchem.2016.05.085] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 05/11/2016] [Accepted: 05/12/2016] [Indexed: 10/21/2022]
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28
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Development of an advanced in vitro model of the stomach and its evaluation versus human gastric physiology. Food Res Int 2016. [DOI: 10.1016/j.foodres.2016.01.030] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Chen L, Xu Y, Fan T, Liao Z, Wu P, Wu X, Chen XD. Gastric emptying and morphology of a ‘near real’ in vitro human stomach model (RD-IV-HSM). J FOOD ENG 2016. [DOI: 10.1016/j.jfoodeng.2016.02.025] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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30
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Guo J, Kaletunç G. Dissolution kinetics of pH responsive alginate-pectin hydrogel particles. Food Res Int 2016; 88:129-139. [PMID: 28847392 DOI: 10.1016/j.foodres.2016.05.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 05/16/2016] [Accepted: 05/21/2016] [Indexed: 11/18/2022]
Abstract
Encapsulation is used for protection of bioactive compounds during processing, storage, and passage through the upper gastrointestinal (GI) tract and delivery to the small intestine. A number of pH responsive synthetic polymers are approved for drug delivery but are not allowed for food applications. We developed a biopolymer mixture composed of alginate and pectin that can form hydrogel when the pH is below 3.0. We also produced novel disc shaped particles which can potentially enhance the particle adhesion in intestines. As the pH increases, Al-P hydrogels go through a gel-sol transition and the dissolution kinetics of the hydrogel dominates the bioactive compound release. The goals of this study are to investigate the relative effects of factors contributing to the dissolution kinetics of Al-P hydrogel and to develop mathematical models characterizing the degradation behavior of the hydrogels under product storage and lower GI tract conditions. The volume change of spherical and disc shaped particles at pH3.0 showed that the hydrogel particles would be stable in low pH beverages during storage. At pH5.0 and 7.0, hydrogel particle dissolution followed a zero-order kinetic model. The 2.8% TGC 43:57wt% Al-P disc particles had the fastest and the 2.2% TGC 82:18wt% Al-P spherical particles had the slowest volume dissolution rate at pH7.0 and 37°C. Activation energies of hydrogel particles were significantly affected by pH, particle shape and Al to P ratio. Such a biopolymer system which responds to pH provides an opportunity to use food as a vehicle for targeted delivery of bioactive compounds.
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Affiliation(s)
- Jingxin Guo
- Department of Food, Agricultural, and Biological Engineering, Ohio State University, Columbus, OH, United States
| | - Gönül Kaletunç
- Department of Food, Agricultural, and Biological Engineering, Ohio State University, Columbus, OH, United States.
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31
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Hutchison AT, Piscitelli D, Horowitz M, Jones KL, Clifton PM, Standfield S, Hausken T, Feinle-Bisset C, Luscombe-Marsh ND. Acute load-dependent effects of oral whey protein on gastric emptying, gut hormone release, glycemia, appetite, and energy intake in healthy men. Am J Clin Nutr 2015; 102:1574-1584. [PMID: 26537944 DOI: 10.3945/ajcn.115.117556] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In healthy individuals, intraduodenal whey protein load-dependently modulates gastrointestinal motor and hormonal functions and suppresses energy intake. The effect of oral whey, particularly the impact of load, has not been evaluated. OBJECTIVE The purpose of this study was to quantify gastric emptying of 30 and 70 g of oral whey protein loads and their relation to gastrointestinal hormone, glycemic, and appetitive responses. DESIGN On 3 separate occasions in a randomized, double-blind order, 18 lean men [mean ± SEM age: 24.8 ± 1.4 y; body mass index (in kg/m(2)): 21.6 ± 0.5] received iso-osmolar, equally palatable drinks (∼450 mL) containing 30 g pure whey protein isolate (L), 70 g pure whey protein isolate (H), or saline (control). Gastric emptying (with the use of 3-dimensional ultrasound), plasma cholecystokinin, glucagon-like peptide 1, glucose-dependent insulinotropic peptide, insulin, glucagon, total amino acids, and blood glucose were measured for 180 min after consumption of the drinks, and energy intake at a buffet-style lunch was quantified. RESULTS Gastric emptying of the L and H drinks was comparable when expressed in kilocalories per minute (L: 2.6 ± 0.2 kcal/min; H: 2.9 ± 0.3 kcal/min) and related between individuals (r = 0.54, P < 0.01). Gastrointestinal hormone, insulin, and glucagon responses to the L and H drinks were comparable until ∼45-60 min after ingestion, after which time the responses became more differentiated. Blood glucose was modestly reduced after the H drink between t = 45 and 150 min when compared with the L drink (all P < 0.05). Energy intake was suppressed by both L and H drinks compared with control (P < 0.05) (control: 1174 ± 91 kcal; L: 1027 ± 81 kcal; and H: 997 ± 71 kcal). CONCLUSION These findings indicate that, in healthy lean men, the rate of gastric emptying of whey protein is independent of load and determines the initial gastrointestinal hormone response. This study was registered at www.anzctr.org.au as 12611000706976.
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Affiliation(s)
- Amy T Hutchison
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Diana Piscitelli
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; School of Health Sciences and
| | - Michael Horowitz
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Karen L Jones
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Peter M Clifton
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
| | - Scott Standfield
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Trygve Hausken
- Institute of Medicine, University of Bergen, and National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; and
| | - Christine Feinle-Bisset
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Natalie D Luscombe-Marsh
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia; National Health and Medical Research Council Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia; Food and Nutrition Flagship, Commonwealth Science and Industrial Research Organization, Adelaide, Australia
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32
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Hutchison AT, Feinle-Bisset C, Fitzgerald PCE, Standfield S, Horowitz M, Clifton PM, Luscombe-Marsh ND. Comparative effects of intraduodenal whey protein hydrolysate on antropyloroduodenal motility, gut hormones, glycemia, appetite, and energy intake in lean and obese men. Am J Clin Nutr 2015; 102:1323-1331. [PMID: 26561615 DOI: 10.3945/ajcn.115.114538] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In lean individuals, intraduodenal protein and lipid modulate gastrointestinal motor and hormone functions and reduce energy intake in a load-dependent manner; protein also stimulates insulin, with modest effects on reducing blood glucose. The effect of intraduodenal lipid on gastrointestinal motor and hormone responses is diminished in obesity; whether the effects of protein are also attenuated remains unclear. OBJECTIVES The objectives of this study were to characterize the load-dependent effects of intraduodenal whey protein hydrolysate on antropyloroduodenal pressures, gut hormones, glycemia, appetite, and energy intake in obese subjects and to compare the responses to the higher protein load with those in lean subjects. DESIGN We measured antropyloroduodenal pressures, plasma cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, insulin, blood glucose, appetite, and energy intake in 12 nondiabetic obese men on 3 separate occasions, in a double-blind, randomized order, during 60-min intraduodenal infusions of hydrolyzed whey protein at either 0 (saline control), 1.5, or 3 kcal/min. Twelve age-matched lean individuals received a 3-kcal/min infusion only. Immediately after the infusions, energy intake from a buffet lunch was quantified. RESULTS In obese subjects, protein suppressed antral and duodenal pressures; stimulated plasma CCK, GLP-1, GIP, insulin, and glucagon (all r > 0.57, P < 0.01); and tended to reduce energy intake (r = -10.38, P = 0.057) in a dose-dependent manner. In response to the 3-kcal/min protein load, antropyloroduodenal pressures, CCK, GLP-1, and glucagon did not differ between lean and obese subjects. Insulin release was greater, and GIP release less, in obese than in lean subjects (both P < 0.05), whereas the reduction in glucose was comparable. Energy intake tended to be higher in obese subjects (P = 0.08). CONCLUSIONS The gastrointestinal effects of hydrolyzed whey protein remain relatively intact in obesity; however, the observed changes in insulin and GIP suggest early disturbances in the insulin-incretin axis. This study was registered at www.anzctr.org.au as ACTRN 12612000203853.
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Affiliation(s)
- Amy T Hutchison
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Christine Feinle-Bisset
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Penelope C E Fitzgerald
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Scott Standfield
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Michael Horowitz
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia
| | - Peter M Clifton
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia; School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia; and
| | - Natalie D Luscombe-Marsh
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council of Australia Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, Australia; Commonwealth Scientific and Industrial Research Organization, Animal, Food and Health Sciences, Adelaide, Australia
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Effect of bread gluten content on gastrointestinal function: a crossover MRI study on healthy humans. Br J Nutr 2015; 115:55-61. [PMID: 26522233 DOI: 10.1017/s0007114515004183] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Gluten is a crucial functional component of bread, but the effect of increasing gluten content on gastrointestinal (GI) function remains uncertain. Our aim was to investigate the effect of increasing gluten content on GI function and symptoms in healthy participants using the unique capabilities of MRI. A total of twelve healthy participants completed this randomised, mechanistic, open-label, three-way crossover study. On days 1 and 2 they consumed either gluten-free bread (GFB), or normal gluten content bread (NGCB) or added gluten content bread (AGCB). The same bread was consumed on day 3, and MRI scans were performed every 60 min from fasting baseline up to 360 min after eating. The appearance of the gastric chime in the images was assessed using a visual heterogeneity score. Gastric volumes, the small bowel water content (SBWC), colonic volumes and colonic gas content and GI symptoms were measured. Fasting transverse colonic volume after the 2-d preload was significantly higher after GFB compared with NGCB and AGCB with a dose-dependent response (289 (SEM 96) v. 212 (SEM 74) v. 179 (SEM 87) ml, respectively; P=0·02). The intragastric chyme heterogeneity score was higher for the bread with increased gluten (AGCB 6 (interquartile range (IQR) 0·5) compared with GFB 3 (IQR 0·5); P=0·003). However, gastric half-emptying time was not different between breads nor were study day GI symptoms, postprandial SBWC, colonic volume and gas content. This MRI study showed novel mechanistic insights in the GI responses to different breads, which are poorly understood notwithstanding the importance of this staple food.
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Abstract
Aging is characterized by a diminished homeostatic regulation of physiologic functions, including slowing of gastric emptying. Gastric and small intestinal motor and humoral mechanisms in humans are complex and highly variable: ingested food is stored, mixed with digestive enzymes, ground into small particles, and delivered as a liquefied form into the duodenum at a rate allowing efficient digestion and absorption. In healthy aging, motor function is well preserved whereas deficits in sensory function are more apparent. The effects of aging on gastric emptying are relevant to the absorption of oral medications and the regulation of appetite, postprandial glycemia, and blood pressure.
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Affiliation(s)
- Stijn Soenen
- Discipline of Medicine, National Health and Medical Research Council of Australia (NHMRC) Centre of Research Excellence in Translating Nutritional Science to Good Health, Royal Adelaide Hospital, The University of Adelaide, Frome Road, Adelaide, South Australia 5000, Australia.
| | - Chris K Rayner
- Discipline of Medicine, National Health and Medical Research Council of Australia (NHMRC) Centre of Research Excellence in Translating Nutritional Science to Good Health, Royal Adelaide Hospital, The University of Adelaide, Frome Road, Adelaide, South Australia 5000, Australia
| | - Michael Horowitz
- Discipline of Medicine, National Health and Medical Research Council of Australia (NHMRC) Centre of Research Excellence in Translating Nutritional Science to Good Health, Royal Adelaide Hospital, The University of Adelaide, Frome Road, Adelaide, South Australia 5000, Australia
| | - Karen L Jones
- Discipline of Medicine, National Health and Medical Research Council of Australia (NHMRC) Centre of Research Excellence in Translating Nutritional Science to Good Health, Royal Adelaide Hospital, The University of Adelaide, Frome Road, Adelaide, South Australia 5000, Australia
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Antoniou AJ, Raja S, El-Khouli R, Mena E, Lodge MA, Wahl RL, Clarke JO, Pasricha P, Ziessman HA. Comprehensive Radionuclide Esophagogastrointestinal Transit Study: Methodology, Reference Values, and Initial Clinical Experience. J Nucl Med 2015; 56:721-7. [DOI: 10.2967/jnumed.114.152074] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/14/2015] [Indexed: 01/27/2023] Open
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Jones RGA, Martino A. Targeted localized use of therapeutic antibodies: a review of non-systemic, topical and oral applications. Crit Rev Biotechnol 2015; 36:506-20. [PMID: 25600465 DOI: 10.3109/07388551.2014.992388] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Therapeutic antibodies provide important tools in the "medicine chest" of today's clinician for the treatment of a range of disorders. Typically monoclonal or polyclonal antibodies are administered in large doses, either directly or indirectly into the circulation, via a systemic route which is well suited for disseminated ailments. Diseases confined within a specific localized tissue, however, may be treated more effectively and at reduced cost by a delivery system which targets directly the affected area. To explore the advantages of the local administration of antibodies, we reviewed current alternative, non-systemic delivery approaches which are in clinical use, being trialed or developed. These less conventional approaches comprise: (a) local injections, (b) topical and (c) peroral administration routes. Local delivery includes intra-ocular injections into the vitreal humor (i.e. Ranibizumab for age-related macular degeneration), subconjunctival injections (e.g. Bevacizumab for corneal neovascularization), intra-articular joint injections (i.e. anti-TNF alpha antibody for persistent inflammatory monoarthritis) and intratumoral or peritumoral injections (e.g. Ipilimumab for cancer). A range of other strategies, such as the local use of antibacterial antibodies, are also presented. Local injections of antibodies utilize doses which range from 1/10th to 1/100th of the required systemic dose therefore reducing both side-effects and treatment costs. In addition, any therapeutic antibody escaping from the local site of disease into the systemic circulation is immediately diluted within the large blood volume, further lowering the potential for unwanted effects. Needle-free topical application routes become an option when the condition is restricted locally to an external surface. The topical route may potentially be utilized in the form of eye drops for infections or corneal neovascularization or be applied to diseased skin for psoriasis, dermatitis, pyoderma gangrenosum, antibiotic resistant bacterial infections or ulcerated wounds. Diseases confined to the gastrointestinal tract can be targeted directly by applying antibody via the injection-free peroral route. The gastrointestinal tract is unusual in that its natural immuno-tolerant nature ensures the long-term safety of repeatedly ingesting heterologous antiserum or antibody materials. Without the stringent regulatory, purity and clean room requirements of manufacturing parenteral (injectable) antibodies, production costs are minimal, with the potential for more direct low-cost targeting of gastrointestinal diseases, especially with those caused by problematic antibiotic resistant or toxigenic bacteria (e.g. Clostridium difficile, Helicobacter pylori), viruses (e.g. rotavirus, norovirus) or inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease). Use of the oral route has previously been hindered by excessive antibody digestion within the gastrointestinal tract; however, this limitation may be overcome by intelligently applying one or more strategies (i.e. decoy proteins, masking therapeutic antibody cleavage sites, pH modulation, enzyme inhibition or encapsulation). These aspects are additionally discussed in this review and novel insights also provided. With the development of new applications via local injections, topical and peroral routes, it is envisaged that an extended range of ailments will increasingly fall within the clinical scope of therapeutic antibodies further expanding this market.
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Affiliation(s)
| | - Angela Martino
- a Department of Chemistry , University of Warwick , Coventry , UK
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Effects of varying the inter-meal interval on relationships between antral area, gut hormones and energy intake following a nutrient drink in healthy lean humans. Physiol Behav 2014; 135:34-43. [DOI: 10.1016/j.physbeh.2014.05.040] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 05/02/2014] [Accepted: 05/28/2014] [Indexed: 02/07/2023]
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Min YW, Hong YS, Ko EJ, Lee JY, Min BH, Sohn TS, Kim JJ, Rhee PL. Impairment of the proximal to distal tonic gradient in the human diabetic stomach. Neurogastroenterol Motil 2014; 26:229-36. [PMID: 24165095 DOI: 10.1111/nmo.12253] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 09/26/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Little has been known about the contractile characteristics of diabetic stomach. We investigated spontaneous contractions and responses to acetylcholine in the gastric muscle in diabetic patients and non-diabetic control subjects according to the region of stomach. METHODS Gastric specimens were obtained from 26 diabetics and 55 controls who underwent gastrectomy at Samsung Medical Center between February 2008 and November 2011. Isometric force measurements were performed using circular muscle strips from the different regions of stomach under basal condition and in response to acetylcholine. KEY RESULTS Basal tone of control was higher in the proximal stomach than in the distal (0.63 g vs 0.46 g, p = 0.027). However, in diabetics, basal tone was not significantly different between the proximal and distal stomach (0.75 g vs 0.62 g, p = 0.32). The distal stomach of diabetics had higher basal tone and lower frequency than that of control (0.62 g vs 0.46 g, p = 0.049 and 4.0/min vs 4.9/min, p = 0.049, respectively). After exposure to acetylcholine, dose-dependent increases of basal tone, peak, and area under the curve (AUC) were noticed in both proximal and distal stomach of the two groups. In the proximal stomach, however, the dose-dependent increase of basal tone and AUC was less prominent in diabetics than in control. CONCLUSIONS & INFERENCES On the contrary to control, the proximal to distal tonic gradient was not observed in diabetic stomach. Diabetic stomach also had lower frequency of spontaneous contraction in the distal stomach and less acetylcholine-induced positive inotropic effect in the proximal stomach than control.
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Affiliation(s)
- Y W Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Horváth VJ, Izbéki F, Lengyel C, Kempler P, Várkonyi T. Diabetic gastroparesis: functional/morphologic background, diagnosis, and treatment options. Curr Diab Rep 2014; 14:527. [PMID: 25005121 DOI: 10.1007/s11892-014-0527-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The regulation of gastrointestinal motility mainly involves the smooth muscle, neural (extrinsic and intrinsic), and hormonal elements, the glial cells, and the interstitial cells of Cajal. An orchestrated function of all these components is required for the appropriate propulsive movement of the food in the gastrointestinal tract. Gastroparesis, a pathological slowing-down of gastric emptying, is a result of the damage to the tissue elements involved in the regulation of motility. Gastroparesis is one of the well-known complications of long-standing diabetes mellitus. Although it is rarely a life-threatening complication, it has a deteriorating effect on the quality of life, leads to unpredictable oscillation of the blood glucose level, and increases the time required for the absorption of food and medicines. This review describes the clinical characteristics of diabetic gastroparesis and summarizes the organic and functional motility abnormalities caused by this complication. Finally, the currently available and potential future therapeutic approaches are summarized.
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Affiliation(s)
- Viktor J Horváth
- 1st Department of Medicine, Semmelweis University, Koranyi Sandor utca 2/a, 1081, Budapest, Hungary,
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Yalcin H, Okuyucu EE, Ucar E, Duman T, Yilmazer S. Changes in liquid emptying in migraine patients: diagnosed with liquid phase gastric emptying scintigraphy. Intern Med J 2013; 42:455-9. [PMID: 22498119 DOI: 10.1111/j.1445-5994.2012.02741.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Gastric stasis is suspected mostly to be encountered during acute migraine attack. The aim of this study is to evaluate the liquid phase gastric emptying and motility in migraine patients in ictal and interictal periods in comparison to normal subjects with gastric emptying scintigraphy. Seven women with migraine and age, sex matched controls who applied to the Neurology Department from May 2009 to May 2010 were compared. Gastric emptying study with a standard liquid was performed one time in the non-migraineur group and two times in the migraineur group. Non-migraineur controls and migraineurs were compared. The mean T1/2 was longer in ictal period in migraineurs. The T1/2 of migraineurs interictally and the control groups were similar. The T1/2 of migraineurs ictally and migraineurs interictally were also compared. We also considered the percentage of the radioactive material remaining in the stomach. There were no significant differences between non-migraineurs and migraineurs interictally. However, increased amount of radioactive material remaining in the stomach was observed in migraineurs ictally. We concluded that the liquid emptying was delayed in spontaneous migraine attacks in migraine without aura, however in the interictal period the emptying of liquids did not differ between migraineurs and non-migraineurs.
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Affiliation(s)
- H Yalcin
- Department of Nuclear Medicine, Mustafa Kemal University School of Medicine, Hatay, Turkey.
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Deane AM, Besanko LK, Burgstad CM, Chapman MJ, Horowitz M, Fraser RJL. Modulation of individual components of gastric motor response to duodenal glucose. World J Gastroenterol 2013; 19:5863-5869. [PMID: 24124331 PMCID: PMC3793140 DOI: 10.3748/wjg.v19.i35.5863] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 05/07/2013] [Accepted: 06/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate individual components of the antro-pyloro-duodenal (APD) motor response to graded small intestinal glucose infusions in healthy humans. METHODS APD manometry was performed in 15 healthy subjects (12 male; 40 ± 5 years, body mass index 26.5 ± 1.6 kg/m(2)) during four 20-min intraduodenal infusions of glucose at 0, 0.5, 1.0 and 1.5 kcal/min, in a randomised double-blinded fashion. Glucose solutions were infused at a rate of 1 mL/min and separated by 40-min "wash-out" period. Data are mean ± SE. Inferential analyses are repeated measure analysis of variance with Bonferroni post-hoc testing. RESULTS At 0 kcal/min frequency of pressure waves were: antrum (7.5 ± 1.8 waves/20 min) and isolated pyloric pressure waves (IPPWs) (8.0 ± 2.3 waves/20 min) with pyloric tone (0.0 ± 0.9 mmHg). Intraduodenal glucose infusion acutely increased IPPW frequency (P < 0.001) and pyloric tone (P = 0.015), and decreased antral wave frequency (P = 0.007) in a dose-dependent fashion. A threshold for stimulation was observed at 1.0 kcal/min for pyloric phasic pressure waves (P = 0.002) and 1.5 kcal/min for pyloric tone and antral contractility. CONCLUSION There is hierarchy for the activation of gastrointestinal motor responses to duodenal glucose infusion. An increase in IPPWs is the first response observed.
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Nguyen NQ, Bryant LK, Burgstad CM, Chapman M, Deane A, Bellon M, Lange K, Bartholomeuz D, Horowitz M, Holloway RH, Fraser RJ. Gastric emptying measurement of liquid nutrients using the (13)C-octanoate breath test in critically ill patients: a comparison with scintigraphy. Intensive Care Med 2013; 39:1238-1246. [PMID: 23471513 DOI: 10.1007/s00134-013-2881-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 02/06/2013] [Indexed: 02/07/2023]
Abstract
PURPOSE Scintigraphy is considered the most accurate technique for the measurement of gastric emptying (GE) but, for patients in the intensive care unit, it is technically demanding, involves radiation and can interfere with care. The (13)C-octanoate breath test ((13)C-OBT) is a simple, non-invasive technique that does not involve radiation exposure. AIM To evaluate the performance of the (13)C-OBT in the assessment of GE in critically ill patients. METHODS The GE was assessed in 33 mechanically ventilated patients (23 M; 54.3 ± 3.0 yrs; APACHE II: 22.0 ± 1.1). Following test meal administration (100 ml Ensure(®)), concurrent scintigraphic measurement and breath samples ((13)C-OBT) were collected over 4 h. Scintigraphic meal retention was determined and the gastric emptying coefficient (GEC) and half emptying time [t50(BT)] were calculated for the (13)C-OBT. Delayed GE was defined as meal retention >13 % at 180 min. RESULTS Delayed GE was identified in 27/33 patients. Meal retention correlated modestly with t50(BT) (r = 0.55-0.66; P < 0.001) and well with GEC (r = -0.63 to -0.74; P < 0.0001). The strength of agreement between the two techniques was highest between GEC and retention at 120 min. The best cut-off GEC for defining delayed GE was 3.25 (AUC = 0.75; 95 % CI = 0.52-0.99; P = 0.05), with 89 % sensitivity and 67 % specificity to detect delayed GE. The GE was delayed in all (23/23) patients with feed intolerance (GRV > 250 ml) on scintigraphy and 91 % (21/23) patients on (13)C-OBT. CONCLUSION In critical illness, there was a correlation between (13)C-OBT and gastric scintigraphy, with GEC performing as a better and more sensitive marker of detecting delayed GE than t50. However the relatively wide 95 % confidence intervals suggest that (13)C-OBT is more suitable as a technique to assess GE in a group setting for research studies rather than for individual patients in clinical practice.
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Affiliation(s)
- Nam Q Nguyen
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
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Marciani L, Pritchard SE, Hellier-Woods C, Costigan C, Hoad CL, Gowland PA, Spiller RC. Delayed gastric emptying and reduced postprandial small bowel water content of equicaloric whole meal bread versus rice meals in healthy subjects: novel MRI insights. Eur J Clin Nutr 2013; 67:754-8. [PMID: 23594839 PMCID: PMC3701291 DOI: 10.1038/ejcn.2013.78] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Revised: 02/19/2013] [Accepted: 02/20/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND/OBJECTIVES Postprandial bloating is a common symptom in patients with functional gastrointestinal (GI) diseases. Whole meal bread (WMB) often aggravates such symptoms though the mechanisms are unclear. We used magnetic resonance imaging (MRI) to monitor the intragastric fate of a WMB meal (11% bran) compared with a rice pudding (RP) meal. SUBJECTS/METHODS Twelve healthy volunteers completed this randomised crossover study. They fasted overnight and after an initial MRI scan consumed a glass of orange juice with a 2267 kJ WMB or an equicaloric RP meal. Subjects underwent serial MRI scans every 45 min up to 270 min to assess gastric volumes and small bowel water content, and completed a GI symptom questionnaire. RESULTS The MRI intragastric appearance of the two meals was markedly different. The WMB meal formed a homogeneous dark bolus with brighter liquid signal surrounding it. The RP meal separated into an upper liquid layer and a lower particulate layer allowing more rapid emptying of the liquid compared with solid phase (sieving). The WMB meal had longer gastric half-emptying times (132±8 min) compared with the RP meal (104±7 min), P<0.008. The WMB meal was associated with markedly reduced MRI-visible small bowel free mobile water content compared with the RP meal, P<0.0001. CONCLUSIONS WMB bread forms a homogeneous bolus in the stomach, which inhibits gastric sieving and hence empties slower than the equicaloric rice meal. These properties may explain why wheat causes postprandial bloating and could be exploited to design foods that prolong satiation.
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Affiliation(s)
- L Marciani
- University of Nottingham, Nottingham, UK
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Demedts I, Masaoka T, Kindt S, De Hertogh G, Geboes K, Farré R, Vanden Berghe P, Tack J. Gastrointestinal motility changes and myenteric plexus alterations in spontaneously diabetic biobreeding rats. J Neurogastroenterol Motil 2013; 19:161-70. [PMID: 23667747 PMCID: PMC3644652 DOI: 10.5056/jnm.2013.19.2.161] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Revised: 12/17/2012] [Accepted: 01/02/2013] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND/AIMS Type 1 diabetes is often accompanied by gastrointestinal motility disturbances. Vagal neuropathy, hyperglycemia, and alterations in the myenteric plexus have been proposed as underlying mechanism. We therefore studied the relationship between vagal function, gastrointestinal motiliy and characteristics of the enteric nervous system in the biobreeding (BB) rat known as model for spontaneous type 1 diabetes. METHODS Gastric emptying breath test, small intestinal electromyography, relative risk-interval variability, histology and immunohistochemistry on antral and jejunal segments were performed at 1, 8 and 16 weeks after diabetes onset and on age-matched controls. RESULTS We observed no consistent changes in relative risk-interval variability and gastric emptying rate. There was however, a loss of phases 3 with longer duration of diabetes on small intestinal electromyography. We found a progressive decrease of nitrergic neurons in the myenteric plexus of antrum and jejunum, while numbers of cholinergic nerve were not altered. In addition, a transient inflammatory infiltrate in jejunal wall was found in spontaneous diabetic BB rats at 8 weeks of diabetes. CONCLUSIONS In diabetic BB rats, altered small intestinal motor control associated with a loss of myenteric nitric oxide synthase expression occurs, which does not depend on hyperglycemia or vagal dysfunction, and which is preceded by transient intestinal inflammation.
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Affiliation(s)
- Ingrid Demedts
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Tatsuhiro Masaoka
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Sebastien Kindt
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Department of Pathology, University of Leuven, Leuven, Belgium
| | - Karel Geboes
- Department of Pathology, University of Leuven, Leuven, Belgium
| | - Ricard Farré
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Pieter Vanden Berghe
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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Rheological Properties and Textural Attributes of Cooked Brown and White Rice During Gastric Digestion in Vivo. FOOD BIOPHYS 2013. [DOI: 10.1007/s11483-013-9288-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Culen M, Rezacova A, Jampilek J, Dohnal J. Designing a dynamic dissolution method: a review of instrumental options and corresponding physiology of stomach and small intestine. J Pharm Sci 2013; 102:2995-3017. [PMID: 23494815 DOI: 10.1002/jps.23494] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Revised: 02/10/2013] [Accepted: 02/13/2013] [Indexed: 11/10/2022]
Abstract
Development of new pharmaceutical compounds and dosage forms often requires in vitro dissolution testing with the closest similarity to the human gastrointestinal (GI) tract. To create such conditions, one needs a suitable dissolution apparatus and the appropriate data on the human GI physiology. This review discusses technological approaches applicable in biorelevant dissolutions as well as the physiology of stomach and small intestine in both fasted and fed state, that is, volumes of contents, transit times for water/food and various solid oral dosage forms, pH, osmolality, surface tension, buffer capacity, and concentrations of bile salts, phospholipids, enzymes, and Ca(2+) ions. The information is aimed to provide clear suggestions on how these conditions should be set in a dynamic biorelevant dissolution test.
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Affiliation(s)
- Martin Culen
- University of Veterinary and Pharmaceutical Sciences Brno, Brno 612 42, Czech Republic.
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Seimon RV, Brennan IM, Russo A, Little TJ, Jones KL, Standfield S, Wishart JM, Horowitz M, Feinle-Bisset C. Gastric emptying, mouth-to-cecum transit, and glycemic, insulin, incretin, and energy intake responses to a mixed-nutrient liquid in lean, overweight, and obese males. Am J Physiol Endocrinol Metab 2013; 304:E294-E300. [PMID: 23211514 DOI: 10.1152/ajpendo.00533.2012] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Observations relating to the impact of obesity on gastric emptying (GE) and the secretion of gut hormones are inconsistent, probably because of a lack of studies in which GE, gastrointestinal hormone release, and energy intake (EI) have been evaluated concurrently with previous patterns of nutrient intake. GE is known to be a major determinant of postprandial glycemia and incretin secretion in health and type 2 diabetes. The aims of this study were to determine the effects of a mixed-nutrient drink on GE, oro-cecal transit, blood glucose, insulin and incretin concentrations and EI, and the relationship between the glycemic response to the drink with GE in lean, overweight, and obese subjects. Twenty lean, 20 overweight, and 20 obese males had measurements of GE, oro-cecal transit, and blood glucose, insulin, GLP-1, and GIP concentrations for 5 h after ingestion of a mixed-nutrient drink (500 ml, 532 kcal); EI at a subsequent buffet lunch was determined. Habitual EI was also quantified. Glycemic and insulinemic responses to the drink were greater in the obese (both P < 0.05) when compared with both lean and overweight, with no significant differences in GE, intragastric distribution, oro-cecal transit, incretins, or EI (buffet lunch or habitual) between groups. The magnitude of the rise in blood glucose after the drink was greater when GE was relatively more rapid (r = -0.55, P < 0.05). In conclusion, in the absence of differences in habitual EI, both GE and incretin hormones are unaffected in the obese despite greater glucose and insulin responses, and GE is a determinant of postprandial glycemia.
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Affiliation(s)
- Radhika V Seimon
- University of Adelaide Discipline of Medicine and National Health and Medical Research Council Centre of Australia Clinical Research Excellence in Nutritional Physiology, Interactions and Outcomes, Adelaide, South Australia, Australia
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Ryan AT, Feinle-Bisset C, Kallas A, Wishart JM, Clifton PM, Horowitz M, Luscombe-Marsh ND. Intraduodenal protein modulates antropyloroduodenal motility, hormone release, glycemia, appetite, and energy intake in lean men. Am J Clin Nutr 2012; 96:474-482. [PMID: 22854403 DOI: 10.3945/ajcn.112.038133] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Intraduodenal fat and carbohydrate modulate antropyloroduodenal motility and hormone release and suppress appetite and energy intake in a load-dependent manner. Protein also suppresses energy intake, but its effects on these gastrointestinal factors and their role in the appetite-suppressive effects of protein remain unclear. OBJECTIVE We aimed to characterize the effects of different intraduodenal protein loads on antropyloroduodenal pressures, gastrointestinal hormone release, glucose and insulin concentrations, appetite perceptions, and energy intake. DESIGN Sixteen lean, healthy men were studied on 4 occasions in a randomized, double-blind fashion. Antropyloroduodenal pressures, plasma glucagon-like peptide 1 (GLP-1), cholecystokinin, peptide YY, ghrelin, blood glucose, serum insulin, and appetite were measured during 60-min, 4-mL/min intraduodenal infusions of protein at 0.5, 1.5, or 3 kcal/min or saline (control). Energy intakes at a buffet lunch consumed immediately after the infusion were quantified. RESULTS Increases in the load of protein resulted in greater suppression of antral motility, greater stimulation of basal and isolated pyloric pressures and plasma cholecystokinin and GLP-1 concentrations, and greater suppression of energy intake. However, energy intake was reduced only after a protein load of 3 kcal/min compared with after all other treatments (P < 0.05). The suppression of energy intake after adjustment for cholecystokinin, GLP-1, and insulin was related inversely with basal pyloric pressure (r = -0.51, P < 0.001). CONCLUSION The acute effects of intraduodenal protein on antropyloroduodenal motility, gastrointestinal hormone release, glucose, and insulin are load dependent and contribute to the suppression of energy intake. This trial was registered at www.anzctr.org.au as 12610000376044.
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Affiliation(s)
- Amy T Ryan
- University of Adelaide Discipline of Medicine, Royal Adelaide Hospital, Adelaide, Australia
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Maurer AH. Advancing gastric emptying studies: standardization and new parameters to assess gastric motility and function. Semin Nucl Med 2012; 42:101-12. [PMID: 22293165 DOI: 10.1053/j.semnuclmed.2011.10.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
For many years, gastric emptying (GE) studies were performed using various local protocols and different radiolabeled meals. This lack of standardization and normal values made the test results unreliable and difficult to compare from one site to another. A recent consensus has been published that now provides guidance and standardization on how to perform a radiolabeled solid-meal GE study. It is widely recognized, however, that simple measurement of total GE of a solid meal often does not provide an answer to the etiology of symptoms for a large number of patients who present with functional dyspepsia. Advances in our understanding of the different roles of the fundus and antrum and their complex interaction with the proximal small bowel and central nervous system have led to the development of new methods to study gastric motility. This review describes how a more comprehensive approach to studying GE is needed and how this will lead to better diagnosis and treatment for patients referred for GE studies.
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Affiliation(s)
- Alan H Maurer
- Department of Radiology, Nuclear Medicine, Temple University Hospital and School of Medicine, Philadelphia, PA 19140, USA.
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Abstract
BACKGROUND Different studies indicated a correlation between intragastric pressure (IGP) and satiation. Our aim was to investigate this correlation while artificially increasing the IGP. METHODS In 12 fasted healthy volunteers an infusion catheter and a manometry probe were positioned intragastrically. Intragastric pressure was increased using a custom-made belt before or progressively during intragastric nutrient infusion. Nutrient drink (1.5 kcal mL(-1)) was intragastrically infused at 60 mL min(-1) . The subjects scored satiation using a 6-point Likert scale until maximum, when the infusion ended and the belt was released. Results are presented as mean ± S.E.M. and compared using a paired t-test. KEY RESULTS When the belt was tightened before the nutrient infusion, fasting IGP was significantly increased (13.6 ± 1.3 vs 9.6 ± 0.9 mmHg; P < 0.05) but no differences in satiation could be observed. When progressively tightening the belt during nutrient infusion the IGP increased with 0.43 ± 0.04 mmHg per minute while in control experiments this was 0.28 ± 0.05 mmHg per minute (P < 0.01). During the latter experiment satiation linearly increased with 0.35 ± 0.03 and 0.29 ± 0.02 units per minute until maximal satiation (P < 0.01) while maximum volume consumed was 926 ± 66 and 1095 ± 82 mL when progressively increasing the IGP vs control respectively (P < 0.01). CONCLUSIONS & INFERENCES These findings indicate that IGP per se does not affect satiation but that a gradual IGP increase during food intake is associated with decreased food intake, indicating that gastric accommodation is an important determinant of food intake.
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Affiliation(s)
- P Janssen
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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