Publications by authors named "Gareth J Sanger"

60 Publications

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

Pharmacol Rev 2021 Jan;73(1):310-520

Neuropharmacology Research Group, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (N.M.B., A.R.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia (N.M.B., D.H.); Department of Pharmacology, Georgetown University Medical Center, Washington, DC (G.P.A.); Institut de Génomique Functionnelle, Université Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France (C.B., J.B., S.C.-D., S.C., P.M.); Université de Montpellier, Montpellier, France (C.B., J.B., S.C.-D., S.C., P.M.); C.E.N.T.E.R. Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota (M.C.); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (K.A.C., R.M.H.); School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, United Kingdom (K.C.F.); Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York (M.G.); Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta (G.D.G.); Department of Physiology, Department of Obstetrics and Gynaecology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (N.M.G., E.K.L.); Department of Psychiatry, University of California San Diego, La Jolla, California (A.L.H.); Theranyx, Marseille, France (G.H.); Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York (K.H.-D.); Ecole Polytechnique Fédérale de Lausanne, Institute of Chemical Sciences and Engineering, Lausanne, Switzerland (R.H., H.V.); Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, Italy (E.L., M.L.); Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway (F.O.L.); Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (S.C.R.L.); INSERM UMR-S 1270, Paris, France (L.M., A.R.); Sorbonne Université, Paris, France (L.M., A.R.); Institut du Fer à Moulin, Paris, France (L.M., A.R.); Drug Development, Grunenthal GmbH, Aachen, Germany (A.C.M.); Tucson, Arizona (D.L.N.); Departments of Psychiatry and Behavioral Sciences and Pharmacology, University of Washington, Seattle, Washington (J.F.N.); Neurolixis Inc., Dana Point, California (A.N.-T.); Université Grenoble Alpes, Institut de Biologie Structurale, Grenoble, France (H.N.); CNRS, Institut de Biologie Structurale, Grenoble, France (H.N.); Commissariat à l'Energie Atomique et aux Energies Alternatives, DSV, Institut de Biologie Structurale, Grenoble, France (H.N.); Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina (B.L.R.); Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom (G.J.S.); Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (M.T.); Department of Pharmacology, University of Oxford, Oxford, United Kingdom (T.S.); Cinvestav-Coapa, Pharmacobiology, Mexico City, Tlalpan, Mexico (C.M.V.); Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W.); The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia (D.H.); and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.).

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/pr.118.015552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770494PMC
January 2021

The Benefits of Olanzapine in Palliating Symptoms.

Curr Treat Options Oncol 2020 Nov 26;22(1). Epub 2020 Nov 26.

Blizard Institute and National Bowel Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, England.

Opinion Statement: Olanzapine has become a major drug in the management of chemotherapy-induced nausea and vomiting as a prophylactic agent. In addition, a recent randomized trial has demonstrated its benefits in treating nausea and vomiting associated with advanced cancer. The added benefit to olanzapine is that it also stimulates appetite. As a result, since it treats multiple symptoms associated with advanced cancer, it is likely to become the antiemetic of choice in palliative care at least in the USA. The added benefit of treating insomnia and the avoidance of benzodiazepines should place olanzapine in at the top of the list of drugs to use for patients who do complain of insomnia. There is no good evidence that it potentiates the respiratory depression of opioids unlike benzodiazepines. The evidence is weak that olanzapine in as an adjuvant analgesic. Hopefully, future trials will explore this in greater depth. The benefits of adding olanzapine to potent opioids are that it may reduce craving, drug cues, and opioid misuse. Other symptoms like anxiety and depression may be addressed by the addition of olanzapine to standard antidepressants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11864-020-00804-1DOI Listing
November 2020

Copeptin, a surrogate marker of arginine vasopressin, has no ability to modulate human and mouse gastric motility.

Eur J Pharmacol 2021 Feb 18;892:173740. Epub 2020 Nov 18.

Bariatric Surgery Department, Homerton University Hospital, London, United Kingdom.

Copeptin, a glycosylated peptide fragment derived from the C-terminal region of the precursor of arginine vasopressin (AVP), is co-secreted with AVP in equimolar amounts. Elevated plasma AVP modulates gastric motility so we investigated whether copeptin had a similar effect. Copeptin (10-10M), and AVP (10-10M), were evaluated for their ability to modulate spontaneous and electrically-evoked (EFS) contractions of human proximal and distal gastric circular muscle in vitro. Similar experiments were performed on the mouse stomach and we re-examined the published effect of copeptin on the mouse aorta. In the presence of tetrodotoxin (10M), atropine (10M) and L-NAME (3 × 10M), human proximal and distal stomach muscle contracted spontaneously and rhythmically as did mouse distal stomach. Copeptin (10-10M), had no effect on baseline muscle tone or myogenic spontaneous contractions of either human or mouse stomach. However, AVP concentration-dependently increased tone, amplitude and frequency of contractions in both regions of human stomach with similar potency (pEC 9.0-9.5; n = 4) and threshold concentration (10-10M). AVP was similarly active in the mouse stomach. EFS-evoked cholinergic contractions (human and mouse) were unaffected by both peptides EFS-evoked relaxations of mouse stomach were unaffected by copeptin. In sub-maximally contracted mouse aorta the elevated tone was unaffected by copeptin (10M) (cf. previously published study) but was reduced by carbachol (10M) and sodium nitroprusside (10M). We conclude that in contrast to AVP, copeptin over a concentration range reported in the plasma has no direct ability to modulate the motility of the human and mouse stomach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2020.173740DOI Listing
February 2021

COVID-19, nausea, and vomiting.

J Gastroenterol Hepatol 2020 Sep 21. Epub 2020 Sep 21.

Blizard Institute and the National Centre for Bowel Research, Barts The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Exclusion of nausea (N) and vomiting (V) from detailed consideration as symptoms of COVID-19 is surprising as N can be an early presenting symptom. We examined the incidence of NV during infection before defining potential mechanisms. We estimate that the overall incidence of nausea (median 10.5%), although variable, is comparable with diarrhea. Poor definition of N, confusion with appetite loss, and reporting of N and/or V as a single entity may contribute to reporting variability and likely underestimation. We propose that emetic mechanisms are activated by mediators released from the intestinal epithelium by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) modulate vagal afferents projecting to the brainstem and after entry into the blood, activate the area postrema (AP) also implicated in anorexia. The receptor for spike protein of SARS-CoV-2, angiotensin 2 converting enzyme (ACE2), and transmembrane protease serine (for viral entry) is expressed in upper gastrointestinal (GI) enterocytes, ACE2 is expressed on enteroendocrine cells (EECs), and SARS-CoV-2 infects enterocytes but not EECs (studies needed with native EECs). The resultant virus-induced release of epithelial mediators due to exocytosis, inflammation, and apoptosis provides the peripheral and central emetic drives. Additionally, data from SARS-CoV-2 show an increase in plasma angiotensin II (consequent on SARS-CoV-2/ACE2 interaction), a centrally (AP) acting emetic, providing a further potential mechanism in COVID-19. Viral invasion of the dorsal brainstem is also a possibility but more likely in delayed onset symptoms. Overall, greater attention must be given to nausea as an early symptom of COVID-19 and for the insights provided into the GI effects of SARS-CoV-2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgh.15261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537541PMC
September 2020

Inhibition of Neuromuscular Contractions of Human and Rat Colon by Bergamot Essential Oil and Linalool: Evidence to Support a Therapeutic Action.

Nutrients 2020 May 12;12(5). Epub 2020 May 12.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 4NS, UK.

Bergamot essential oil (BEO) added to food and drink promotes a citrus flavour. Folklore suggests benefits on gastrointestinal functions but with little supporting evidence. BEO and major constituents (linalool, limonene, linalyl acetate) were therefore examined for any ability to influence neuromuscular contractions of human and rat colon. Circular muscle strips (macroscopically-normal human colon obtained following ethical approval at cancer surgery; Sprague-Dawley rats) were suspended in baths (Krebs solution; 37 °C; 5% CO in O) for measurement of neuronally-mediated contractions (prevented by tetrodotoxin or atropine) evoked by electrical field stimulation (5 Hz, 0.5 ms pulse width, 10s/minute, maximally-effective voltage), or contractions evoked by KCl (submaximally-effective concentrations). BEO and each constituent concentration dependently inhibited neuronally-mediated and KCl-induced contractions. In human: apparent IC for BEO (volume/volume Krebs), respectively, 3.8 ± 0.3 and 4.4 ± 0.3; I 55.8% ± 4.2% and 37.5% ± 4.2%. For the constituents, the rank order of potency differed in human (linalool > limonene > linalyl-acetate) and rat colon (linalyl-acetate > limonene = linalool), but rank order of efficacy was similar (linalool > (BEO) = linalyl-acetate > limonene). Thus, linalool had high efficacy but greater potency in human colon (I 76.8% ± 6.9%; pIC 6.7 ± 0.2; = 4) compared with rat colon (I 75.3% ± 1.9%; pIC 5.8 ± 0.1; = 4). The ability of BEO and linalool to inhibit human colon neuromuscular contractility provides a mechanism for use as complementary treatments of intestinal disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12051381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284490PMC
May 2020

Reversal of Pathogen-Induced Barrier Defects in Intestinal Epithelial Cells by Contra-pathogenicity Agents.

Dig Dis Sci 2021 Jan 7;66(1):88-104. Epub 2020 Feb 7.

Barts and The London School of Medicine, Queen Mary, University of London, London, E1 2AT, UK.

Background: Environmental enteropathy (EE) is associated with stunting, impairment of responses to oral vaccines, and other adverse health consequences in young children throughout the developing world. EE is characterized by chronic low-grade intestinal inflammation and disrupted epithelial barrier integrity, partly resulting from dysregulation of tight junction proteins, observed in other enteropathies such as celiac disease. During EE, this dysregulation of tight junction expression amplifies translocation of pathogenic bacteria across the intestinal mucosa.

Aims: The aim was to determine whether enteropathogen-mediated epithelial barrier failure can be ameliorated using contra-pathogenicity therapies.

Methods: Intestinal epithelial barrier damage was assessed in Caco-2 cells incubated with three important enteropathogens identified in EE patients: Enteropathogenic Escherichia coli (EPEC), Citrobacter rodentium (C. rodentium), and Cryptosporidium parvum (C. parvum). Potential therapeutic molecules were tested to detect effects on transepithelial resistance (TER), bacterial translocation (BT), claudin-4 expression, and regulation of the inflammatory cytokine response.

Results: All three enteropathogens compared to uninfected cells, reduced TER (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0007), reduced claudin-4 expression, and permitted BT (EPEC; p < 0.0001, C. rodentium; p < 0.0001, C. parvum; p < 0.0003) through the monolayer. Zinc, colostrum, epidermal growth factor, trefoil factor 3, resistin-like molecule-β, hydrocortisone, and the myosin light chain kinase inhibitor ML7 (Hexahydro-1-[(5-iodo-1-naphthalenyl)sulfonyl]-1H-1,4-diazepine hydrochloride); ML7) improved TER (up to 70%) and decreased BT (as much as 96%). Only zinc demonstrated modest antimicrobial activity.

Conclusion: The enteropathogens impaired intestinal-epithelial barrier integrity with dysregulation of claudin-4 and increased bacterial translocation. Enteropathogen-mediated damage was reduced using contra-pathogenicity agents which mitigated the effects of pathogens without direct antimicrobial activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10620-020-06121-9DOI Listing
January 2021

Functional and anatomical deficits in visceral nociception with age: a mechanism of silent appendicitis in the elderly?

Pain 2020 04;161(4):773-786

Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking health care and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and noninflamed appendixes were collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single-unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of calcitonin gene-related peptide-positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single-unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrate that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/j.pain.0000000000001764DOI Listing
April 2020

Functional brain networks and neuroanatomy underpinning nausea severity can predict nausea susceptibility using machine learning.

J Physiol 2019 03 27;597(6):1517-1529. Epub 2019 Feb 27.

Centre for Neuroscience and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, 26 Ashfield Street, London, E1 2AJ, UK.

Key Points: Nausea is an adverse experience characterised by alterations in autonomic and cerebral function. Susceptibility to nausea is difficult to predict, but machine learning has yet to be applied to this field of study. The severity of nausea that individuals experience is related to the underlying morphology (shape) of the subcortex, namely of the amygdala, caudate and putamen; a functional brain network related to nausea severity was identified, which included the thalamus, cingulate cortices (anterior, mid- and posterior), caudate nucleus and nucleus accumbens. Sympathetic nervous system function and sympathovagal balance, by heart rate variability, was closely related to both this nausea-associated anatomical variation and the functional connectivity network, and machine learning accurately predicted susceptibility or resistance to nausea. These novel anatomical and functional brain biomarkers for nausea severity may permit objective identification of individuals susceptible to nausea, using artificial intelligence/machine learning; brain data may be useful to identify individuals more susceptible to nausea.

Abstract: Nausea is a highly individual and variable experience. The central processing of nausea remains poorly understood, although numerous influential factors have been proposed, including brain structure and function, as well as autonomic nervous system (ANS) activity. We investigated the role of these factors in nausea severity and if susceptibility to nausea could be predicted using machine learning. Twenty-eight healthy participants (15 males; mean age 24 years) underwent quantification of resting sympathetic and parasympathetic nervous system activity by heart rate variability. All were exposed to a 10-min motion-sickness video during fMRI. Neuroanatomical shape differences of the subcortex and functional brain networks associated with the severity of nausea were investigated. A machine learning neural network was trained to predict nausea susceptibility, or resistance, using resting ANS data and detected brain features. Increasing nausea scores positively correlated with shape variation of the left amygdala, right caudate and bilateral putamen (corrected P = 0.05). A functional brain network linked to increasing nausea severity was identified implicating the thalamus, anterior, middle and posterior cingulate cortices, caudate nucleus and nucleus accumbens (corrected P = 0.043). Both neuroanatomical differences and the functional nausea-brain network were closely related to sympathetic nervous system activity. Using these data, a machine learning model predicted susceptibility to nausea with an overall accuracy of 82.1%. Nausea severity relates to underlying subcortical morphology and a functional brain network; both measures are potential biomarkers in trials of anti-nausea therapies. The use of machine learning should be further investigated as an objective means to develop models predicting nausea susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP277474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418775PMC
March 2019

A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research.

Front Pharmacol 2018 4;9:913. Epub 2018 Sep 4.

Division of Biomedical Sciences, St George's University of London, London, United Kingdom.

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) -originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) -searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) -investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) metoclopramide was initially assumed to act only via D receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT receptors. The latter led to identification of selective 5-HT receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) -antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.00913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131675PMC
September 2018

Investigational drug therapies for the treatment of gastroparesis.

Expert Opin Investig Drugs 2017 Mar 7;26(3):331-342. Epub 2017 Feb 7.

b Vice Chair of Medicine for Innovation and Commercialization , Johns Hopkins University School of Medicine, Director, Johns Hopkins Center for Neurogastroenterology, Professor of Medicine and Neurosciences, Professor of Innovation Management, Johns Hopkins Carey School of Business , Baltimore , MD , USA.

Introduction: Gastroparesis is defined by nausea, vomiting, pain, early satiety and bloating, and characterized by delayed gastric emptying without obvious structural abnormalities. Metoclopramide is widely used, increasing gastric emptying and inhibiting nausea and vomiting. Other drugs are available in certain countries and some are used 'off-label' because they increase gastric emptying or inhibit emesis. However, correlation between gastroparesis symptoms and rates of gastric emptying is poor. For anti-emetic drugs, dose-ranging and Phase III trials in gastroparesis are lacking. Areas covered: Gastric motility may still be disordered, leading to nausea, even though gastric emptying is unchanged. One hypothesis is that interstitial cells of Cajal (ICC) are damaged by diabetes leading to gastric dysrhythmia and nausea. Novel approaches to treatment of nausea also include the use of ghrelin receptor agonists, highlighting a link between appetite and nausea. Expert opinion: There is an urgent need to diversify away from historical drug targets. In particular, there is a need to control nausea by regulating ICC functions and/or by facilitating appetite via ghrelin receptor agonists. It is also important to note that different upper gastrointestinal disorders (gastroparesis, chronic unexplained nausea and vomiting, functional dyspepsia) are difficult to distinguish apart, suggesting wider therapeutic opportunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13543784.2017.1288214DOI Listing
March 2017

Ghrelin and Motilin Control Systems in GI Physiology and Therapeutics.

Handb Exp Pharmacol 2017 ;239:379-416

Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia.

Ghrelin and motilin are released from gastrointestinal endocrine cells during hunger, to act through G protein-coupled receptors that have closely related amino acid sequences. The actions of ghrelin are more complex than motilin because ghrelin also exists outside the GI tract, it is processed to des-acyl ghrelin which has activity, ghrelin can exist in truncated forms and retain activity, the ghrelin receptor can have constitutive activity and is subject to biased agonism and finally additional ghrelin-like and des-acyl ghrelin receptors are proposed. Both ghrelin and motilin can stimulate gastric emptying, acting via different pathways, perhaps influenced by biased agonism at the receptors, but research is revealing additional pathways of activity. For example, it is becoming apparent that reduction of nausea may be a key therapeutic target for ghrelin receptor agonists and perhaps for compounds that modulate the constitutive activity of the ghrelin receptor. Reduction of nausea may be the mechanism through which gastroparesis symptoms are reduced. Intriguingly, a potential ability of motilin to influence nausea is also becoming apparent. Ghrelin interacts with digestive function through its effects on appetite, and ghrelin antagonists may have a place in treating Prader-Willi syndrome. Unlike motilin, ghrelin receptor agonists also have the potential to treat constipation by acting at the lumbosacral defecation centres. In conclusion, agonists of both ghrelin and motilin receptors hold potential as treatments for specific subsets of digestive system disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/164_2016_104DOI Listing
October 2017

Ex vivo study of human visceral nociceptors.

Gut 2018 01 21;67(1):86-96. Epub 2016 Sep 21.

National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Objective: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation.

Design: Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV) modulation on mechanical responses.

Results: Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity.

Conclusions: Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/gutjnl-2016-311629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754853PMC
January 2018

Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design.

Sci Rep 2016 08 5;6:30797. Epub 2016 Aug 5.

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.

If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant κ opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi-effectively activated both receptors, assessed by measuring two different cell signalling pathways which were equally affected without evidence of bias. In mouse intestine, naturally expressing κ receptors within its nervous system, both compounds also equi-effectively activated the receptor, inhibiting nerve-mediated muscle contraction. However, whereas ICI204448 acted similarly in human intestine, where κ receptors are again expressed within its nervous system, asimadoline was inhibitory only at very high concentrations; instead, low concentrations of asimadoline reduced the activity of ICI204448. This demonstration of species-dependence in activation of native, not recombinant κ receptors may be explained by different mouse/human receptor structures affecting receptor expression and/or interactions with intracellular signalling pathways in native environments, to reveal differences in intrinsic efficacy between receptor agonists. These results have profound implications in drug design for κ and perhaps other receptors, in terms of recombinant-to-native receptor translation, species-dependency and possibly, a need to use human, therapeutically-relevant, not surrogate tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep30797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974614PMC
August 2016

Chronic constipation: improved understanding offers a new therapeutic approach.

Authors:
Gareth J Sanger

J Physiol 2016 08;594(15):4085-7

Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/JP272560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967749PMC
August 2016

The pharmacodynamics, safety and pharmacokinetics of single doses of the motilin agonist, camicinal, in type 1 diabetes mellitus with slow gastric emptying.

Br J Pharmacol 2016 06 13;173(11):1768-77. Epub 2016 Apr 13.

GlaxoSmithKline, Research Triangle Park, NC, USA.

Background And Purpose: Here we have investigated the pharmacokinetics, pharmacodynamics and safety of single doses of camicinal in type 1 diabetes mellitus (T1DM) patients with a history of slow gastric emptying with symptoms consistent with gastroparesis.

Experimental Approach: In a randomized, double-blind, placebo-controlled, incomplete block, three-period, two-centre crossover study, patients received oral administration of placebo and two of the three possible doses of camicinal (25, 50 or 125 mg). Gastric emptying ((13) C-octanoic acid breath test), pharmacokinetics and safety were primary outcomes.

Key Results: Nine of the 10 patients enrolled completed the study. Gastric half-emptying time decreased by -95 min (95% CI: -156.8, -34.2) after a single dose of camicinal 125 mg compared with placebo (52 vs. 147 min, P < 0.05), representing a 65% improvement. A decrease of the gastric half-emptying time compared with placebo (approximately 39 min) was observed with camicinal 25 and 50 mg, representing a 27% reduction for both doses (not statistically significant). A positive exposure-response relationship was demonstrated across all doses. The effects of camicinal on gastric half-emptying time were not influenced by fasting glucose levels. Single doses up to 125 mg were well tolerated. Camicinal was well absorbed, exhibiting linear and approximately dose-proportional pharmacokinetic characteristics and a clear exposure-response relationship with gastric emptying.

Conclusions And Implications: Camicinal significantly accelerated gastric emptying of solids in T1DM patients following administration of a single oral dose. Camicinal was well tolerated and exhibited similar pharmacokinetic characteristics in diabetic patients to those previously reported in healthy volunteers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.13475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867742PMC
June 2016

RQ-00201894: A motilin receptor agonist causing long-lasting facilitation of human gastric cholinergically-mediated contractions.

J Pharmacol Sci 2016 Feb 19;130(2):60-5. Epub 2015 Nov 19.

Blizard Institute (National Centre for Bowel Research and Surgical Innovation), Barts and the London School of Medicine and Dentistry, 2 Newark Street, London, E1 2AT, UK. Electronic address:

The aim was to characterise RQ-00201894, a novel non-macrolide motilin agonist, using human recombinant receptors and then investigate its ability to facilitate cholinergic activity in human stomach. A reporter gene assay assessed motilin receptor function. Selectivity of action was determined using a panel of different receptors, ion channels, transporters and enzymes. Cholinergically-mediated muscle contractions were evoked by electrical field stimulation (EFS) of human gastric antrum. The results showed that RQ-00201894, motilin and erythromycin acted as full motilin receptor agonists (EC50: 0.20, 0.11, 69 nM, respectively). In this function, RQ-00201894 had >90-fold selectivity of action over its ability to activate the human ghrelin receptor (EC50 19 nM) and greater selectivity over all other receptors/mechanisms tested. In human stomach RQ-00201894 0.1-30 μM concentration-dependently increased EFS-evoked contractions (up to 1209%; pEC50 6.0). At 0.1-10 μM this activity was usually prolonged. At higher concentrations (3-30 μM) RQ-00201894 also caused a short-lasting muscle contraction, temporally disconnected from the increase in EFS-evoked contractions. RQ-00201894 10 μM did not consistently affect submaximal contractions evoked by carbachol. In conclusion, RQ-00201894 potently and selectively activates the motilin receptor and causes long-lasting facilitation of cholinergic activity in human stomach, an activity thought to correlate with an ability to increase gastric emptying.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jphs.2015.11.004DOI Listing
February 2016

Ghrelin and motilin receptors as drug targets for gastrointestinal disorders.

Nat Rev Gastroenterol Hepatol 2016 Jan 22;13(1):38-48. Epub 2015 Sep 22.

Department of Anatomy and Neuroscience, University of Melbourne, VIC 3010, Australia.

The gastrointestinal tract is the major source of the related hormones ghrelin and motilin, which act on structurally similar G protein-coupled receptors. Nevertheless, selective receptor agonists are available. The primary roles of endogenous ghrelin and motilin in the digestive system are to increase appetite or hedonic eating (ghrelin) and initiate phase III of gastric migrating myoelectric complexes (motilin). Ghrelin and motilin also both inhibit nausea. In clinical trials, the motilin receptor agonist camicinal increased gastric emptying, but at lower doses reduced gastroparesis symptoms and improved appetite. Ghrelin receptor agonists have been trialled for the treatment of diabetic gastroparesis because of their ability to increase gastric emptying, but with mixed results; however, relamorelin, a ghrelin agonist, reduced nausea and vomiting in patients with this disorder. Treatment of postoperative ileus with a ghrelin receptor agonist proved unsuccessful. Centrally penetrant ghrelin receptor agonists stimulate defecation in animals and humans, although ghrelin itself does not seem to control colorectal function. Thus, the most promising uses of motilin receptor agonists are the treatment of gastroparesis or conditions with slow gastric emptying, and ghrelin receptor agonists hold potential for the reduction of nausea and vomiting, and the treatment of constipation. Therapeutic, gastrointestinal roles for receptor antagonists or inverse agonists have not been identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrgastro.2015.163DOI Listing
January 2016

Analysis of the ghrelin receptor-independent vascular actions of ulimorelin.

Eur J Pharmacol 2015 Apr 14;752:34-9. Epub 2015 Feb 14.

Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia.

Ulimorelin (TZP101) is a ghrelin receptor agonist that stimulates intestinal motility, but also reduces blood pressure in rodents and humans and dilates blood vessels. It has been proposed as a treatment for intestinal motility disorders. Here we investigated the mechanisms through which ulimorelin affects vascular diameter. Actions of ulimorelin on wall tension of rodent arteries were investigated and compared with other ghrelin receptor agonists. Saphenous, mesenteric and basilar arteries were obtained from Sprague-Dawley rats (male, 8 weeks) and saphenous arteries were obtained from wild type or ghrelin receptor null mice. These were mounted in myography chambers to record artery wall tension. Ulimorelin (0.03-30µM) inhibited phenylephrine-induced contractions of rat saphenous (IC50=0.6µM; Imax=66±5%; n=3-6) and mesenteric arteries (IC50=5µM, Imax=113±16%; n=3-4), but not those contracted by U46619, ET-1 or 60mM [K(+)]. Relaxation of phenylephrine-constricted arteries was not observed with ghrelin receptor agonists TZP102, capromorelin or AZP-531. In rat saphenous and basilar arteries, ulimorelin (10-100µM) and TZP102 (10-100µM) constricted arteries (EC50=9.9µM; Emax=50±7% and EC50=8µM; Emax=99±16% respectively), an effect not attenuated by the ghrelin receptor antagonist YIL 781 3µM or mimicked by capromorelin or AZP-531. In mesenteric arteries, ulimorelin, 1-10µM, caused a surmountable rightward shift in the response to phenylephrine (0.01-1000µM; pA2=5.7; n=3-4). Ulimorelin had similar actions in mouse saphenous artery from both wild type and ghrelin receptor null mice. We conclude that ulimorelin causes vasorelaxation through competitive antagonist action at α1-adrenoceptors and a constrictor action not mediated via the ghrelin receptor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2015.02.005DOI Listing
April 2015

Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans.

J Physiol 2015 Mar 29;593(5):1183-96. Epub 2015 Jan 29.

Centre for Digestive Diseases, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, E1 2AJ, UK; University Hospitals of North Midlands, Stoke on Trent, Staffordshire, ST4 6QG, UK.

An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1113/jphysiol.2014.284240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358679PMC
March 2015

Nausea and the quest for the perfect anti-emetic.

Eur J Pharmacol 2014 Jan 22;722:108-21. Epub 2013 Oct 22.

National Centre for Bowel Research & Surgical Innovation, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, E1 2AT, UK.

The discovery of anti-emetic agents is reviewed to illustrate the large database (>129,000 papers in PubMed) available for potential data mining and to provide a background to the shift in interest to nausea from vomiting. Research on nausea extends to identification of biomarkers for diagnosis/clinical trials and to understanding why nausea is such a common dose-limiting toxicity of diverse therapeutic agents. The lessons learned for translation from animals to humans, from the discovery of the anti-vomiting effects of 5-HT3 and NK1 receptor antagonists, is discussed in terms of the similarities between the emetic pathways and their pharmacology, and also in terms of the limitations of rodent models of "nausea" (pica, conditioned taste aversion, conditioned gaping and disgust). The review focuses on the established view that anti-emetics are more efficacious against vomiting than nausea. In particular we examine studies of 5-HT3, NK1 and D2 receptor antagonists, gabapentin and various receptor agonists. The potential for targeting anti-nausea agents is then considered, by targeting mechanisms which correct delayed gastric emptying (prokinetics), the rise in plasma vasopressin (AVP) and/or act at central targets revealed by the growing knowledge of cortical regions activated/inhibited in subjects reporting nausea. Modulation of the projections from the brainstem to the cortical areas responsible for the genesis of the sensation of nausea provides the most likely approach to a target at which an anti-nausea drug could be targeted with the expectation that it would affect nausea from multiple causes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2013.09.072DOI Listing
January 2014

The relationship between gastric motility and nausea: gastric prokinetic agents as treatments.

Eur J Pharmacol 2013 Sep 4;715(1-3):10-4. Epub 2013 Jul 4.

Neurogastroenterology Group, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, 2 Newark Street, London, E1 2AT, UK.

Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying. The mechanisms and treatments are unclear (anti-emetic drugs are not fully effective against nausea). Can nausea be relieved by stimulating gastric emptying? Physostigmine (together with atropine) has been shown experimentally to stimulate gastric motility, relieve nausea and restore normal gastric motility. Is this mimicked by gastric prokinetic drugs? The answer is complicated by mixed pharmacology. Metoclopramide increases gastric motility by activating myenteric 5-HT4 receptors but also directly inhibits vomiting via D2 and 5-HT3 receptor antagonism; relationships between increased gastric motility and relief from nausea are therefore unclear. Similarly, the D2 receptor antagonist domperidone has direct anti-emetic activity. Nevertheless, more selective 5-HT4 and motilin receptor agonists (erythromycin, directly stimulating gastric motility) inhibit vomiting in animals; low doses of erythromycin can also relieve symptoms in patients with gastroparesis. Ghrelin stimulates gastric motility and appetite mostly via vagus-dependent pathways, and inhibits vomiting in animals. To date, ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis. We conclude that nausea can be relieved by gastric prokinetic drugs, but more clinical studies are needed using drugs with selective activity. Other mechanisms (e.g. ghrelin, vagal and central pathways, influencing a mechanistic continuum between appetite and nausea) also require exploration. These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology, which focusses on mechanisms of nausea and vomiting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2013.06.031DOI Listing
September 2013

Anti-emetic and emetic effects of erythromycin in Suncus murinus: role of vagal nerve activation, gastric motility stimulation and motilin receptors.

Eur J Pharmacol 2013 Jan 28;699(1-3):48-54. Epub 2012 Nov 28.

School of Applied Sciences, Division of Pharmacy and Pharmaceuticals Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK.

Paradoxically, erythromycin is associated with nausea when used as an antibiotic but at lower doses erythromycin activates motilin receptors and is used to treat delayed gastric emptying and nausea. The aim of this study was to characterise pro- and anti-emetic activity of erythromycin and investigate mechanisms of action. Japanese House musk shrews (Suncus murinus) were used. Erythromycin was administered alone or prior to induction of emesis with abnormal motion or subcutaneous nicotine (10mg/kg). The effects of erythromycin and motilin on vagal nerve activity and on cholinergically mediated contractions of the stomach (evoked by electrical field stimulation) were studied in vitro. The results showed that erythromycin (1 and 5mg/kg) reduced vomiting caused by abnormal motion (e.g., from 10.3 ± 1.8 to 4.0 ± 1.1 emetic episodes at 5mg/kg) or by nicotine (from 9.5 ± 2.0 to 3.1 ± 2.0 at 5mg/kg), increasing latency of onset to emesis; lower or higher doses had no effects. When administered alone, erythromycin 100mg/kg induced vomiting in two of four animals, whereas lower doses did not. In vitro, motilin (1, 100 nM) increased gastric vagal afferent activity without affecting jejunal afferent mesenteric nerve activity. Cholinergically mediated contractions of the stomach (prevented by tetrodotoxin 1 μM or atropine 1 μM, facilitated by l-NAME 300 μM) were facilitated by motilin (1-100 nM) and erythromycin (10-30 μM). In conclusion, low doses of erythromycin have anti-emetic activity. Potential mechanisms of action include increased gastric motility (overcoming gastric stasis) and/ or modulation of vagal nerve pathways involved in emesis, demonstrated by first-time direct recording of vagal activation by motilin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2012.11.035DOI Listing
January 2013

The antibiotic azithromycin is a motilin receptor agonist in human stomach: comparison with erythromycin.

Br J Pharmacol 2013 Apr;168(8):1859-67

Neurogastroenterology Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background And Purpose: The antibiotic azithromycin is a suggested alternative to erythromycin for treating patients with delayed gastric emptying. However, although hypothesized to activate motilin receptors, supportive evidence is unavailable. This was investigated using recombinant and naturally expressed motilin receptors in human stomach, comparing azithromycin with erythromycin.

Experimental Approach: [(125)I]-motilin binding and calcium flux experiments were conducted using human recombinant motilin receptors in CHO cells. Neuromuscular activities were studied using circular muscle of human gastric antrum, after electrical field stimulation (EFS) of intrinsic nerves.

Key Results: Azithromycin (1-100 μM) and erythromycin (3-30 μM) concentration-dependently displaced [(125)I]-motilin binding to the motilin receptor (52 ± 7 and 58 ± 18% displacement at 100 and 30 μM respectively). Azithromycin, erythromycin and motilin concentration-dependently caused short-lived increases in intracellular [Ca(2+)] in cells expressing the motilin receptor. EC50 values were, respectively, 2.9, 0.92 and 0.036 μM (n = 3 each); and maximal activities were similar. In human stomach, EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. Azithromycin and erythromycin lactobionate (30-300 μM each) facilitated these contractions (apparent E(max) values of 2007 ± 396 and 1924 ± 1375%, n = 3-4 each concentration, respectively). These actions were slow in onset and faded slowly. The higher concentrations also evoked short-lived muscle contraction. Contractions to a submaximally effective concentration of carbachol were unaffected by either drug.

Conclusions And Implications: Azithromcyin activates human recombinant motilin receptors in therapeutically relevant concentrations, similar to erythromycin. In humans, gastric antrum azithromycin caused long-lasting facilitation of cholinergic activity. These actions explain the gastric prokinetic activity of azithromycin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.12077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623056PMC
April 2013

The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression.

Naunyn Schmiedebergs Arch Pharmacol 2013 Jan 24;386(1):41-9. Epub 2012 Nov 24.

Department of Medical Sciences, Gastroenterology & Hepatology unit, Building 40, Uppsala University, 751 85, Uppsala, Sweden.

YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5 days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4 h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5 days in the presence of pentagastrin was 1.83 (±0.06). YF476 raised pH to 3.67 (±0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00210-012-0812-5DOI Listing
January 2013

New target profiling for gastrointestinal disorders: where are we going?

Authors:
Gareth J Sanger

Curr Opin Pharmacol 2012 Dec 2;12(6):629-31. Epub 2012 Nov 2.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.coph.2012.10.006DOI Listing
December 2012

Motilin receptor neuropharmacology: revised understanding.

Authors:
Gareth J Sanger

Curr Opin Pharmacol 2012 Dec 2;12(6):641-6. Epub 2012 Aug 2.

Neurogastroenterology Group, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom.

Although motilin was identified >40 years ago as a gastrointestinal hormone capable of stimulating gastric emptying, the relatively recent availability of molecular tools and focus on its neuronal activities are now clarifying mechanisms of action. In rodents, only motilin receptor pseudogenes are identified. In human stomach, facilitation of enteric cholinergic activity is identified as the main mechanism by which gastric emptying is increased; some motilin agonists act in a prolonged manner, contrasting with motilin itself and with studies using recombinant receptors. As such, assays using recombinant receptors seem poor predictors of in vivo activity. High-throughput screening enabled selective motilin agonists to be identified, which together with enhanced understanding into neuromuscular actions of motilin, promises to deliver rational treatments of disorders with delayed gastric emptying.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.coph.2012.07.012DOI Listing
December 2012

The translational value of rodent gastrointestinal functions: a cautionary tale.

Trends Pharmacol Sci 2011 Jul 29;32(7):402-9. Epub 2011 Apr 29.

Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 26 Ashfield Street, London, E1 2AJ, UK.

Understanding relationships between gene complements and physiology is important, especially where major species-dependent differences are apparent. Molecular and functional differences between rodents (rats, mice, guinea pigs) and humans are increasingly reported. Recently, the motilin gene, which encodes a gastrointestinal hormone widely detected in mammals, was found to be absent in rodents where the receptors are pseudogenes; however, actions of motilin in rodents are sometimes observed. Although ghrelin shares common ancestry with motilin, major species-dependent abberations are not reported. The apparently specific absence of functional motilin in rodents is associated with specialised digestive physiology, including loss of ability to vomit; motilin is functional in mammals capable of vomiting. The exception is rabbit, the only other mammal unable to vomit, in which motilin might be conserved to regulate caecotrophy, another specialised digestive process. Motilin illustrates a need for caution when translating animal functions to humans. Nevertheless, motilin receptor agonists are under development as gastroprokinetic drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tips.2011.03.009DOI Listing
July 2011

Challenges and prospects for pharmacotherapy in functional gastrointestinal disorders.

Therap Adv Gastroenterol 2010 Sep;3(5):291-305

Neurogastroenterology Group, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.

Functional gastrointestinal disorders, such as irritable bowel syndrome and functional dyspepsia, are complex conditions with multiple factors contributing to their pathophysiology. As a consequence they are difficult to treat and have posed significant challenges to the pharmaceutical industry when trying to develop new and effective treatments. This review provides an overview of these difficulties and how the industry is reshaping its drug developmental strategies. It describes some of the more significant and encouraging advances that have occurred, and discusses how future research might embrace the opportunities provided by advances in genetic and in particular, epigenetic research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1756283X10369922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002590PMC
September 2010

The hungry stomach: physiology, disease, and drug development opportunities.

Front Pharmacol 2010 18;1:145. Epub 2011 Feb 18.

Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London London, UK.

During hunger, a series of high-amplitude contractions of the stomach and small intestine (phase III), which form part of a cycle of quiescence and contractions (known as the migrating motor complex, MMC), play a "housekeeping" role prior to the next meal, and may contribute toward the development of hunger. Several gastrointestinal (GI) hormones are associated with phase III MMC activity, but currently the most prominent is motilin, thought to at least partly mediate phase III contractions of the gastric MMC. Additional GI endocrine and neuronal systems play even more powerful roles in the development of hunger. In particular, the ghrelin-precursor gene is proving to have a complex physiology, giving rise to three different products: ghrelin itself, which is formed from a post-translational modification of des-acyl-ghrelin, and obestatin. The receptors acted on by des-acyl-ghrelin and by obestatin are currently unknown but both these peptides seem able to exert actions which oppose that of ghrelin, either indirectly or directly. An increased understanding of the actions of these peptides is helping to unravel a number of different eating disorders and providing opportunities for the discovery of new drugs to regulate dysfunctional gastric behaviors and appetite. To date, ghrelin and motilin receptor agonists and antagonists have been described. The most advanced are compounds which activate the ghrelin and motilin receptors which are being progressed for disorders associated with gastric hypomotility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2010.00145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174087PMC
November 2011

Gastrointestinal pharmacology: challenges ahead.

Authors:
Gareth J Sanger

Front Pharmacol 2010 21;1. Epub 2010 May 21.

Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2010.00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095375PMC
July 2011