G J Sanger

Queen Mary, University of London, Londinium, England, United Kingdom

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Publications (159)690.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Motilin agonists promote human gastric motility and cholinergic activity, but excitatory and inhibitory actions are reported in the esophagus. The effect of 5-HT4 agonists in esophagus is also unclear. Perhaps the use of drugs with additional actions explains the variation. The aim, therefore, was to examine how motilin and prucalopride, selective motilin and 5-HT4 receptor agonists, modulate neuromuscular functions in human esophagus and gastric fundus.Methods Electrical field stimulation (EFS) evoked nerve-mediated contractions of circular and longitudinal muscle from human esophageal body and circular muscle from gastric fundus.Key ResultsIn esophageal circular muscle EFS evoked brief contraction, followed by another contraction on termination of EFS, each prevented by atropine. Nitric oxide synthase inhibition facilitated contraction during EFS and the overall contraction became monophasic. In esophagus longitudinal muscle and gastric fundus, EFS evoked cholinergically mediated, monophasic contractions, attenuated by simultaneous nitrergic activation. Motilin (100–300 nM) reduced esophagus circular muscle contractions during EFS, unaffected by L-NAME or apamin. Motilin 300 nM also reduced EFS-evoked contractions of longitudinal muscle. Similar concentrations of motilin facilitated cholinergic activity in the fundus and increased baseline muscle tension. Prucalopride facilitated EFS-evoked contractions in esophagus (tested at 30 μM) and fundus (0.1–30 μM).Conclusions & InferencesSelective motilin and 5-HT4 agonists have different, region-dependent abilities to modulate human esophageal and stomach neuromuscular activity, exemplified by weak inhibition (motilin) or excitation (5-HT4) in esophageal body and excitation for both in stomach. In different patients with motility dysfunctions, motilin and 5-HT4 agonists may reduce gastro-esophageal reflux in different ways.
    Neurogastroenterology and Motility 07/2014; · 2.94 Impact Factor
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    ABSTRACT: Background Progress in identifying safer, effective drugs to increase gastric emptying is impeded by failed clinical trials. One potential reason for failure is lack of translation from animal models to the human condition. To make progress, the actions of existing drugs and new therapeutic candidates need to be understood in human isolated stomach.Methods Neuromuscular activities were evoked in human gastric antrum circular muscle by electrical field stimulation (EFS), defined phenotypically using pharmacological tools.Key ResultsEFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. The 5-HT4 receptor agonist/D2 antagonist metoclopramide and the selective 5-HT4 agonist prucalopride, facilitated contractions in the absence (respectively, Emax 95 ± 29% and 42 ± 9%, n = 3–6 each concentration) and presence (139 ± 38%, 55 ± 13%, n = 3–5) of the NO synthase inhibitor L-NAME, without affecting submaximal contractions to carbachol; the 5-HT4 antagonist SB204070 prevented facilitation by metoclopramide 100 μM (respectively, −5 (range −26 to 34) and 167 (12–1327)% in presence and absence; n = 5–6). The selective motilin receptor agonist camicinal provided considerably greater facilitation (478 (12–2080)% at 30 μM, n = 8). Domperidone (0.001–100 μM; n = 3–6) and acylated or des-acylated ghrelin (1–300 nM; n = 2–4) had no consistent activity, even with protease inhibitors.Conclusions & Inferences5-HT4 receptor agonists show different efficacies. Motilin receptor activation has greater potential to increase gastric emptying, whereas ghrelin and D2 receptor antagonism have no direct activity. Drugs stimulating human gastric motility directly can act regardless of disease mechanisms, whereas drugs without direct activity but an ability to block nausea/vomiting may be effective only if these symptoms exist.
    Neurogastroenterology and Motility 04/2014; · 2.94 Impact Factor
  • G J Sanger
    The American Journal of Gastroenterology 03/2014; 109(3):444-5. · 9.21 Impact Factor
  • G J Sanger
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    ABSTRACT: Ghrelin and motilin receptor agonists increase gastric motility and are attractive drug targets. However, 14 years after the receptors were described (18-24 years since ligands became available) the inactivity of the ghrelin agonist TZP-102 in patients with gastroparesis joins the list of unsuccessful motilin agonists. Fundamental questions must be asked. Pustovit et al., have now shown that the ghrelin agonist ulimorelin evokes prolonged increases in rat colorectal propulsion yet responses to other ghrelin agonists fade. Similarly, different motilin agonists induce short- or long-lasting effects in a cell-dependent manner. Together, these and other data create the hypothesis that the receptors can be induced to preferentially signal ('biased agonism') via particular pathways to evoke different responses with therapeutic advantages/disadvantages. Biased agonism has been demonstrated for ghrelin. Are motilin agonists which cause long-lasting facilitation of human stomach cholinergic function (compared with motilin) biased agonists (e.g., camicinal, under development for patients with gastric hypo-motility)? For ghrelin, additional complications exist because the therapeutic aims/mechanisms of action are uncertain, making it difficult to select the best (biased) agonist. Will ghrelin agonists be useful treatments of nausea and/or as suggested by Pustovit et al., chronic constipation? How does ghrelin increase gastric motility? As gastroparesis symptoms poorly correlate with delayed gastric emptying (yet gastro-prokinetic drugs can provide relief: e.g., low-dose erythromycin), would low doses of ghrelin and motilin agonists relieve symptoms simply by restoring neuromuscular rhythm? These questions on design and functions need addressing if ghrelin and motilin agonists are to reach patients as drugs.
    Neurogastroenterology and Motility 02/2014; 26(2):149-55. · 2.94 Impact Factor
  • Paul L R Andrews, Gareth J Sanger
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    ABSTRACT: 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.
    European journal of pharmacology 10/2013; · 2.59 Impact Factor
  • G J Sanger
    Neurogastroenterology and Motility 10/2013; · 2.94 Impact Factor
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    ABSTRACT: Cholinesterase inhibitors such as neostigmine are used for acute colonic pseudo-obstruction, but cardio-bronchial side-effects limit use. To minimise side-effects, lower doses could be combined with a 5-HT4 receptor agonist, which also facilitates intestinal cholinergic activity. However, safety concerns, especially in the elderly, require drugs with good selectivity of action. These include the acetylcholinesterase inhibitor donepezil (used for Alzheimer's disease, with reduced cardio-bronchial liability) and prucalopride, the first selective, clinically-available 5-HT4 receptor agonist. This study examined their individual and potential synergistic activities in human colon. Neuronally-mediated muscle contractions and relaxations of human colon were evoked by electrical field stimulation (EFS) and defined phenotypically as cholinergic, nitrergic or tachykinergic using pharmacological tools; the effects of drugs were determined as changes in 'area under the curve'. Prucalopride increased cholinergically-mediated contractions (EC50 855 nM; 33% maximum increase), consistent with its ability to stimulate intestinal motility; donepezil (477%) and neostigmine (2326%) had greater efficacy. Concentrations of donepezil (30-100 nM) found in venous plasma after therapeutic doses had minimal ability to enhance cholinergic activity. However, donepezil (30 nM) together with prucalopride (3, 10 μM) markedly increased EFS-evoked contractions compared to prucalopride alone (P=0.04). For example, the increases observed with donepezil and prucalopride 10 μM together or alone were, respectively, 105 ± 35%, 4 ± 6% and 35 ± 21% (n=3-7, each concentration). Potential synergy between prucalopride and donepezil activity calls for exploration of this combination as a safer, more effective treatment of colonic pseudo-obstruction.
    British Journal of Pharmacology 09/2013; · 5.07 Impact Factor
  • Gareth J Sanger, John Broad, Paul L R Andrews
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    ABSTRACT: 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 the mechanisms of emesis.
    European journal of pharmacology 07/2013; · 2.59 Impact Factor
  • John Broad, Gareth J Sanger
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    ABSTRACT: 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 (respectively, 52 ± 7 and 58 ± 18 % displacement at 100 and 30 μM). Azithromycin, erythromycin and motilin concentration-dependently caused short-lived increases in intracellular [Ca(2+) ] in cells expressing the motilin receptor. EC(50) 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 (respectively, apparent E(max) values of 2007 ± 396 and 1924 ± 1375 %, n=3-4 each concentration). 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 human gastric antrum azithromycin caused long-lasting facilitation of cholinergic activity. These actions explain the gastric prokinetic activity of azithromycin.
    British Journal of Pharmacology 11/2012; · 5.07 Impact Factor
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    ABSTRACT: 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 characterize 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 (eg, 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 2 of 4 animals whereas lower doses did not. In vitro, motilin (1, 100nM) increased gastric vagal afferent activity without affecting jejunal afferent mesenteric nerve activity. Cholinergically-mediated contractions of the stomach (prevented by tetrodotoxin 1μM or atropine 1μM, facilitated by L-NAME 300μM) were facilitated by motilin (1-100nM) and erythromycin (10-30μM). 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.
    European journal of pharmacology 11/2012; · 2.59 Impact Factor
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    ABSTRACT: 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.
    Archiv für Experimentelle Pathologie und Pharmakologie 11/2012; · 2.15 Impact Factor
  • Gareth J Sanger
    Current Opinion in Pharmacology 11/2012; · 5.44 Impact Factor
  • Gareth J Sanger
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    ABSTRACT: 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.
    Current Opinion in Pharmacology 08/2012; · 5.44 Impact Factor
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    ABSTRACT: Delayed gastric emptying symptoms are often reported after chemotherapy. This study aims to characterise the effects of chemotherapy on gastric neuro-muscular function. Patients undergoing elective surgery for oesophago-gastric cancer were recruited. Acetylcholinesterase, nNOS, ghrelin receptor and motilin expressions were studied in gastric sections from patients receiving no chemotherapy (n = 3) or oesophageal (n = 2) or gastric (n = 2) chemotherapy. A scoring system quantified staining intensity (0-3; no staining to strong). Stomach sections were separately suspended in tissue baths for electrical field stimulation (EFS) and exposure to erythromycin or carbachol; three patients had no chemotherapy; four completed cisplatin-based chemotherapy within 6 weeks prior to surgery. AChE expression was markedly decreased after chemotherapy (scores 2.3 ± 0.7, 0.5 ± 0.2 and 0 ± 0 in non-chemotherapy, oesophageal- and gastric-chemotherapy groups (p < 0.03 each) respectively. Ghrelin receptor and motilin expression tended to increase (ghrelin: 0.7 ± 0.4 vs 2.0 ± 0.4 and 1.2 ± 0.2 respectively; p = 0.04 and p = 0.2; motilin: 0.7 ± 0.5 vs 2.2 ± 0.5 and 2.0 ± 0.7; p = 0.06 and p = 0.16). Maximal contraction to carbachol was 3.7 ± 0.7 g and 1.9 ± 0.8 g (longitudinal muscle) and 3.4 ± 0.4 g and 1.6 ± 0.6 (circular) in non-chemotherapy and chemotherapy tissues respectively (p < 0.05 each). There were loss of AChE and reduction in contractility to carbachol. The tendency for ghrelin receptors to increase suggests an attempt to upregulate compensating systems. Our study offers a mechanism by which chemotherapy markedly alters neuro-muscular gastric function.
    Molecular Biology Reports 06/2012; · 2.51 Impact Factor
  • Neurogastroenterology and Motility 01/2012; 24:39-40. · 2.94 Impact Factor
  • Gastroenterology 01/2012; 142(5):S105-S105. · 12.82 Impact Factor
  • Gut 01/2012; 61:A317-A318. · 10.73 Impact Factor
  • Source
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    ABSTRACT: GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated. The effect of intravenous GSK962040 on gastro-duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC-MS/MS) and potency of GSK962040 at the dog recombinant receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells]. GSK962040 activated the dog motilin receptor (pEC(50) 5.79; intrinsic activity 0.72, compared with [Nle(13) ]-motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg(-1) ), driven by mean plasma concentrations >1.14 μmol L(-1) . After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg(-1) GSK962040 but at 6 mg kg(-1) , MMCs returned 253 min after dosing, compared with 101 min after saline (n=5 each). The results are consistent with lower potency for agonists at the dog motilin receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species.
    Neurogastroenterology and Motility 10/2011; 23(10):958-e410. · 2.94 Impact Factor
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    ABSTRACT: 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.
    Trends in Pharmacological Sciences 04/2011; 32(7):402-9. · 9.25 Impact Factor
  • Gastroenterology 01/2011; 140(5). · 12.82 Impact Factor

Publication Stats

3k Citations
690.03 Total Impact Points

Institutions

  • 2009–2014
    • Queen Mary, University of London
      Londinium, England, United Kingdom
    • University of Oxford
      Oxford, England, United Kingdom
  • 2006–2013
    • St George's, University of London
      • Division of Biomedical Sciences
      Londinium, England, United Kingdom
    • The Chinese University of Hong Kong
      Hong Kong, Hong Kong
  • 2012
    • University of Huddersfield
      • School of Applied Sciences
      Huddersfield, ENG, United Kingdom
  • 2003–2010
    • University of Melbourne
      Melbourne, Victoria, Australia
    • University College London
      • Department of Cell and Developmental Biology
      London, ENG, United Kingdom
  • 2003–2009
    • GlaxoSmithKline plc.
      • • Medicines Research Centre
      • • Neurology and Gastrointestinal Centre of Excellence for Drug Discovery
      • • Neurology Centre of Excellence for Drug Discovery
      London, ENG, United Kingdom
  • 2008
    • University of Gothenburg
      • Department of Physiology
      Göteborg, Vaestra Goetaland, Sweden
  • 2007–2008
    • University of London
      Londinium, England, United Kingdom
  • 1988–2005
    • St. George's School
      • Department of Physiology
      Middletown, Rhode Island, United States
  • 2002
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
  • 1995
    • The University of Sheffield
      • Department of Biomedical Science
      Sheffield, ENG, United Kingdom