Publications by authors named "Simon Campbell"

49 Publications

Discovery of a Novel Bromodomain and Extra Terminal Domain (BET) Protein Inhibitor, I-BET282E, Suitable for Clinical Progression.

J Med Chem 2021 Aug 13;64(16):12200-12227. Epub 2021 Aug 13.

GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.

The functions of the bromodomain and extra terminal (BET) family of proteins have been implicated in a wide range of diseases, particularly in the oncology and immuno-inflammatory areas, and several inhibitors are under investigation in the clinic. To mitigate the risk of attrition of these compounds due to structurally related toxicity findings, additional molecules from distinct chemical series were required. Here we describe the structure- and property-based optimization of the tool molecule I-BET151 toward I-BET282E, a molecule with properties suitable for progression into clinical studies.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00855DOI Listing
August 2021

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to parasite resistance.

Sci Transl Med 2021 07;13(603)

Sanofi, Infectious Diseases Therapeutic Area, Marcy l'Etoile, France.

The emergence and spread of resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.
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http://dx.doi.org/10.1126/scitranslmed.abg6013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530196PMC
July 2021

Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents.

RSC Med Chem 2020 Aug 25;11(11):1267-1274. Epub 2020 Aug 25.

Institute of Chemistry, University of Campinas (UNICAMP) Rua Josué de Castro, S/N, Cidade Universitária Campinas SP 13083-861 Brazil +55 19 3521 3097.

A series of benzene sulphonamides with good potency and selectivity against spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound . Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series.
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http://dx.doi.org/10.1039/d0md00165aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126888PMC
August 2020

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling.

PLoS Negl Trop Dis 2021 02 22;15(2):e0009196. Epub 2021 Feb 22.

Institute of Chemistry, University of Campinas (UNICAMP), Campinas-SP, Brazil.

Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 μM) and 39 (L. infantum IC50: 0.5 μM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.
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http://dx.doi.org/10.1371/journal.pntd.0009196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932521PMC
February 2021

Substituted Aminoacetamides as Novel Leads for Malaria Treatment.

ChemMedChem 2019 07 3;14(14):1329-1335. Epub 2019 Jul 3.

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.

Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.
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http://dx.doi.org/10.1002/cmdc.201900329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899483PMC
July 2019

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems.

Magn Reson Imaging 2019 06 12;59:121-129. Epub 2019 Mar 12.

Bayer AG, Research and Development, Pharmaceuticals, MR and CT Contrast Media Research, Müllerstraße 178, D-13353 Berlin, Germany. Electronic address:

Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R, but evidence for between-site reproducibility of R in small-animal MRI is lacking.

Objective: To assess R repeatability and multi-site reproducibility in phantoms for preclinical MRI.

Methods: R was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured.

Results: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R-based MR biomarkers were found to be quite sensitive even to such small errors in R, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni in 2% agarose varied between 0.66 s mM at 3 T and 0.94 s mM at 11.7T.

Interpretation: While several factors affect the reproducibility of R-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R-reproducibility.
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http://dx.doi.org/10.1016/j.mri.2019.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477178PMC
June 2019

2,3,8-Trisubstituted Quinolines with Antimalarial Activity.

An Acad Bras Cienc 2018 21;90(1 Suppl 2):1215-1231. Epub 2018 May 21.

Instituto de Química, Universidade Estadual de Campinas, Campinas, SP, Brazil.

Combination therapy drugs are considered a fundamental way to control malaria as it mimimizes the risk of emergence of resistance to the individual partner drugs. Consequently, this type of therapy constitutes a driving force for the discovery of new drugs with different modes of action, since this will provide options for combining different drugs to achieve the optimum antimalarial treatment. In this context, a 2,3,8-trisubstitued quinoline compound was found in a high throughput screen (HTS) to show an excellent inhibition of P. falciparum NF54 (IC50 = 22 nM) and low cytotoxicity. We performed a detailed evaluation of the substituents to improve the metabolic stability and solubility liabilities of the original hit and identified derivatives with enhanced physicochemical and/or PK properties and that maintained biological activity. However the high potency was not retained on testing against drug resistant plasmodium strains.
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http://dx.doi.org/10.1590/0001-3765201820170820DOI Listing
June 2018

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

Nat Commun 2017 05 24;8:15159. Epub 2017 May 24.

Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, P.O. Box 1826, 1215 Geneva, Switzerland.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
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http://dx.doi.org/10.1038/ncomms15159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458052PMC
May 2017

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

Lancet Gastroenterol Hepatol 2016 12 30;1(4):273-282. Epub 2016 Aug 30.

Gastrointestinal Unit, Aberdeen Royal Infirmary, Aberdeen, UK.

Background: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease.

Methods: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15).

Findings: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; p=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group.

Interpretation: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence.

Funding: Medical Research Council.
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http://dx.doi.org/10.1016/S2468-1253(16)30078-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358144PMC
December 2016

Novel inhibitors of Plasmodium falciparum based on 2,5-disubstituted furans.

Eur J Med Chem 2017 Jan 11;126:929-936. Epub 2016 Dec 11.

Instituto de Química, Universidade Estadual de Campinas, Barão Geraldo, PO Box 6154, Campinas, SP 13084-971, Brazil. Electronic address:

Phenotypic HTS campaigns with a blood stage malaria assay have been used to discover novel chemotypes for malaria treatment with potential alternative mechanisms of action compared to existing agents. N-(5-(3-Chloro-4-fluorophenyl)furan-2-yl)-N,N-dimethylpropane-1,3-diamine, 1 was identified as a modest inhibitor of P. falciparum NF54 (IC = 875 nM) with an apparent long plasma half-life after high dose oral administration to mice, although the compound later showed poor metabolic stability in liver microsomes through ring- and side chain-oxidation and N-dealkylation. We describe here the synthesis of derivatives of 1, exploring the influence of substitution patterns around the aromatic ring, variations on the alkyl chain and modifications in the core heterocycle, in order to probe potency and metabolic stability, where 4k showed a long half-life in rats.
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http://dx.doi.org/10.1016/j.ejmech.2016.12.024DOI Listing
January 2017

Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy.

J Med Chem 2016 11 10;59(21):9672-9685. Epub 2016 Sep 10.

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency. Improvement of the pharmacokinetic profile led to several compounds showing excellent oral efficacy in the P. berghei malaria mouse model with ED values below 1 mg/kg when dosed orally for 4 days. The favorable potency, selectivity, DMPK properties, and efficacy coupled with a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 (DDD107498) to preclinical development.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108032PMC
November 2016

Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials.

J Med Chem 2016 07 17;59(13):6101-20. Epub 2016 Jun 17.

Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , Dundee, DD1 5EH, U.K.

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947981PMC
July 2016

Effectiveness of an Adaptive Quizzing System as an Institutional-Wide Strategy to Improve Student Learning and Retention.

Nurse Educ 2016 Sep-Oct;41(5):246-51

Author Affiliations: Assistant Professor (Dr Simon-Campbell), School of Nursing, Sam Houston State University, Texas; and Senior Researcher (Dr Phelan), National Center for Research on Evaluation, Standards, and Student Testing, University of California at Los Angeles.

Exploring ways to help students achieve success in nursing programs is critical to increase retention and the number of nurse graduates. This study examined the impact of an adaptive quizzing system implemented as a strategy to support student persistence and performance measured by use, grades, and graduation. Results indicated that use of the system increased course content mastery and predicted final course grades. Retention and program completion rates were also positively influenced.
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http://dx.doi.org/10.1097/NNE.0000000000000258DOI Listing
April 2017

A novel multiple-stage antimalarial agent that inhibits protein synthesis.

Nature 2015 06;522(7556):315-20

Department of Life Sciences, Imperial College, London SW7 2AZ, UK.

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
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http://dx.doi.org/10.1038/nature14451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700930PMC
June 2015

Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation.

Immunity 2015 May 12;42(5):903-15. Epub 2015 May 12.

Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK; Manchester Immunology Group, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK. Electronic address:

Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation.
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http://dx.doi.org/10.1016/j.immuni.2015.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448149PMC
May 2015

Pulmonary edema measured by MRI correlates with late-phase response to allergen challenge.

Exp Lung Res 2015 May 6;41(4):189-98. Epub 2015 Apr 6.

1Division of Pharmacology, Cardiff School of Pharmacy & Pharmaceutical Science, Cardiff University, Cardiff, United Kingdom.

Purpose: Asthma is associated with reversible airway obstruction, leucocyte infiltration, airways hyperresponsiveness (AHR), and airways remodeling. Fluid accumulation causes pulmonary edema contributing to airways obstruction. We examined the temporal relationship between the late asthmatic response (LAR) following allergen challenge of sensitized guinea-pigs and pulmonary edema measured by magnetic resonance imaging (MRI).

Materials And Methods: Ovalbumin (OVA) sensitized guinea-pigs received either a single OVA inhalation (acute) or nine OVA inhalations at 48 h intervals (chronic). Airways obstruction was measured as specific airways conductance (sG(aw)) by whole body plethysmography. AHR to inhaled histamine and bronchoalveolar lavage for leucocyte counts were measured 24 h after a single or the final chronic ovalbumin challenges. MRI was performed at intervals after OVA challenge and high-intensity edemic signals were quantified.

Results: Ovalbumin caused early bronchoconstriction, followed at 7 h by an LAR and at 24 h AHR and leucocyte influx. The bright-intensity MRI edema signal, peaking at 7 h, was significantly (P < .05) greater after chronic (9.0 ± 0.7 × 10(3) mm(3)) than acute OVA (7.6 ± 0.2 × 10(3) mm(3)). Dexamethasone treatment before acute OVA abolished the AHR and LAR and significantly reduced eosinophils and the bright-intensity MRI edema from 9.1 ± 1.0 to 6.4 ± 0.3 × 10(3) mm(3).

Conclusion: We show a temporal relationship between edema and the LAR and their parallel reduction, along with eosinophils and AHR, by dexamethasone. This suggests a close causative association between pulmonary edema and impaired airways function.
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http://dx.doi.org/10.3109/01902148.2014.985407DOI Listing
May 2015

Assessing quality of life in Crohn's disease: development and validation of the Crohn's Life Impact Questionnaire (CLIQ).

Qual Life Res 2015 Sep 22;24(9):2279-88. Epub 2015 Feb 22.

Galen Research Ltd, Enterprise House, Manchester Science Park, Lloyd Street North, Manchester, M15 6SE, UK,

Purpose: Despite the significant impact of Crohn's disease (CD) on patients' physical and emotional well-being, no CD-specific patient-reported outcome (PRO) measure is available for determining the efficacy of interventions. The objective of the study was to develop and validate the Crohn's Life Impact Scale (CLIQ), the first such measure.

Methods: Questionnaire content was derived from qualitative interviews with CD patients and face and content validity assessed by cognitive debriefing interviews (CDIs) with patients. A postal survey was conducted to identify the final scale, confirm its unidimensionality and determine reproducibility and construct validity. A subset of the respondents was sent a second questionnaire package 2 weeks after the first. The survey included the CLIQ, Nottingham Health Profile (NHP) and Unidimensional Fatigue Impact Scale (U-FIS).

Results: Content analysis was conducted on the 30 interview transcripts and a draft scale produced. The CDIs indicated that the draft scale was relevant, clear and easy to use. The questionnaire package was completed by 273 CD patients (65.6 % male; aged 16-79 (mean 43.9; SD 15.1) years). Of these, 104 also completed the second package. Rasch analysis confirmed a 27-item unidimensional QoL scale (p < 0.05). Both internal consistency and test-retest reliability were high (0.91). Scores on the CLIQ were related to both physical and emotional impairments (NHP) and to fatigue (U-FIS).

Conclusion: The CLIQ, the first CD-specific PRO, is unidimensional and has excellent psychometric properties. It should prove to be a valuable tool for evaluating the impact of CD and its treatment from the patients' perspective.
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http://dx.doi.org/10.1007/s11136-015-0947-1DOI Listing
September 2015

Disease status, patient quality of life and healthcare resource use for ulcerative colitis in the UK: an observational study.

Frontline Gastroenterol 2014 Jul 24;5(3):183-189. Epub 2014 Jan 24.

Merck & Co., Inc., Global Health Outcomes, Whitehouse Station, New Jersey, USA.

Background: Ulcerative colitis is a lifelong, chronic, relapsing-remitting disease.

Objective: To assess the relationship between ulcerative colitis disease status and patient quality of life, and to determine the impact of ulcerative colitis on healthcare costs and work productivity, in the UK.

Methods: Clinicians assessed 173 adult patients' current disease status at a single study visit using the partial Mayo (pMayo) instrument. Patients completed the Euro Quality of Life 5-dimension, 5-level (EQ-5D-5L) questionnaire, the Work Productivity and Activity Impairment (WPAI) questionnaire. Healthcare resource use was determined from questionnaires and from patients' medical charts.

Results: Patients in remission had a significantly higher EQ-5D-5L scores (mean (SD) 0.86 (0.15)) than patients with active disease (0.71 (0.20); p<0.001). Patients with mild disease had significantly higher mean (SD) EQ-5D-5L scores than patients with moderate/severe disease: 0.77 (0.11) and 0.66 (0.24), respectively (p<0.001). The mean percent productivity impairment was greater for patients with active disease than for patients in remission on all items of the WPAI questionnaire: 24.6% vs 1.8% for work time missed, 34.1% vs 12.9% for impairment while working, 40.8% vs 14.4% for overall work impairment and 42.7% vs 13.0% for activity impairment (p<0.001 for all comparisons). The mean (SD) total cost of healthcare for ulcerative colitis in the prior 3 months was £1211 (1588).

Conclusions: When compared with patients in remission, patients with active ulcerative colitis have significantly worse quality of life and significantly more work impairment. The healthcare costs of ulcerative colitis are considerable.
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http://dx.doi.org/10.1136/flgastro-2013-100409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369729PMC
July 2014

An unusual cause of gastrointestinal bleeding: there is more than meets the eye.

Gastroenterology 2013 Oct 20;145(4):729, 915. Epub 2013 Aug 20.

Gastroenterology Unit, Manchester Royal Infirmary, Manchester, United Kingdom.

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http://dx.doi.org/10.1053/j.gastro.2013.07.005DOI Listing
October 2013

Iron deficiency anaemia in young males: do gastrointestinal symptoms and haemoglobin level affect diagnostic yield?

Dig Dis Sci 2013 Oct 6;58(10):3059-60. Epub 2013 Aug 6.

Department of Gastroenterology and Liver Unit, Manchester Royal Infirmary, Oxford Road, Mancheser, M13 9WL, UK,

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http://dx.doi.org/10.1007/s10620-013-2799-2DOI Listing
October 2013

Longitudinal characterization of a model of chronic allergic lung inflammation in mice using imaging, functional and immunological methods.

Clin Sci (Lond) 2013 Dec;125(12):555-64

Respiratory Therapeutic Area, GlaxoSmithKline, Stevenage, Hertfordshire, UK.

The present study investigated the role that imaging could have for assessing lung inflammation in a mouse model of HDM (house dust mite)-provoked allergic inflammation. Inflammation is usually assessed using terminal procedures such as BAL (bronchoalveolar lavage) and histopathology; however, MRI (magnetic resonance imaging) and CT (computed tomography) methods have the potential to allow longitudinal, repeated study of individual animals. Female BALB/c mice were administered daily either saline, or a solution of mixed HDM proteins sufficient to deliver a dose of 12 or 25 μg total HDM protein±budesonide (1 mg/kg of body weight, during weeks 5-7) for 7 weeks. AHR (airway hyper-responsiveness) and IgE measurements were taken on weeks 3, 5 and 7. Following imaging sessions at weeks 3, 5 and 7 lungs were prepared for histology. BAL samples were taken at week 7 and lungs prepared for histology. MRI showed a gradual weekly increase in LTI (lung tissue intensity) in animals treated with HDM compared with control. The 25 μg HDM group showed a continual significant increase in LTI between weeks 3 and 7, the 12 μg HDM-treated group showed a similar rate of increase, and plateaued by week 5. A corresponding increase in AHR, cell counts and IgE were observed. CT showed significant increases in lung tissue density from week 1 of HDM exposure and this was maintained throughout the 7 weeks. Budesonide treatment reversed the increase in tissue density. MRI and CT therefore provide non-invasive sensitive methods for longitudinally assessing lung inflammation. Lung tissue changes could be compared directly with the classical functional and inflammatory readouts, allowing more accurate assessments to be made within each animal and providing a clinically translatable approach.
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http://dx.doi.org/10.1042/CS20130086DOI Listing
December 2013

Sodium content as a predictor of the advanced evolution of globular cluster stars.

Nature 2013 Jun 29;498(7453):198-200. Epub 2013 May 29.

Monash Centre for Astrophysics, School of Mathematical Sciences, Monash University, Melbourne, Victoria 3800, Australia.

The asymptotic giant branch (AGB) phase is the final stage of nuclear burning for low-mass stars. Although Milky Way globular clusters are now known to harbour (at least) two generations of stars, they still provide relatively homogeneous samples of stars that are used to constrain stellar evolution theory. It is predicted by stellar models that the majority of cluster stars with masses around the current turn-off mass (that is, the mass of the stars that are currently leaving the main sequence phase) will evolve through the AGB phase. Here we report that all of the second-generation stars in the globular cluster NGC 6752--70 per cent of the cluster population--fail to reach the AGB phase. Through spectroscopic abundance measurements, we found that every AGB star in our sample has a low sodium abundance, indicating that they are exclusively first-generation stars. This implies that many clusters cannot reliably be used for star counts to test stellar evolution timescales if the AGB population is included. We have no clear explanation for this observation.
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http://dx.doi.org/10.1038/nature12191DOI Listing
June 2013

An exploration of the follow-up up needs of patients with inflammatory bowel disease.

J Crohns Colitis 2013 Oct 27;7(9):e386-95. Epub 2013 Mar 27.

University of Manchester, UK.

Background And Aims: The rising incidence of inflammatory bowel disease (IBD) in adults and children has implications for the lifelong burden of disease and the provision of specialist services. Patients with IBD should have access to specialist care which is delivered according to their values and needs. Few studies have examined patients' views of follow-up care. The aim of this qualitative study was to explore patients' needs, preferences and views of follow-up care.

Methods: IBD patients were selected from a gastroenterology clinic in a UK Hospital and invited to participate in interviews which focused on needs, preferences and role of follow-up, their experience of follow-up, service delivery, and other models of follow-up care.

Results: 24 patients were recruited, 18 patients had Crohn's Disease, and 6 ulcerative colitis. Median age was 48.5 years (range was 27-72 years) and median disease duration 11.5 years (range 2-40 years). Four main themes emerged: (1) experiences of current follow-up care; (2) attitudes to new models of care, including self-management, role of general practitioner, patient-initiated consultations and 'virtual' follow-up; (3) the personal value of follow-up care; and (4) the 'ideal' consultation.

Conclusion: The main finding was that patients prefer a more flexible follow-up care system. 'Virtual' care as an adjunct to patient-initiated consultations and self-management, was identified as optimal approaches to meet the patients' needs of follow-up care. New models of follow-up care could improve the patients' experience of care, offer potential cost savings with reduction in face-to-face consultations and allow targeted care to those who need it.
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http://dx.doi.org/10.1016/j.crohns.2013.03.001DOI Listing
October 2013

Effect of the TRPV1 antagonist SB-705498 on the nasal parasympathetic reflex response in the ovalbumin sensitized guinea pig.

Br J Pharmacol 2013 Jun;169(3):580-9

Platform Technology and Science, GlaxoSmithKline, Stevenage, UK.

Background And Purpose: Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB-705498 as an intranasal therapy for rhinitis.

Experimental Approach: The inhibitory effect of SB-705498 on capsaicin-induced currents in guinea pig trigeminal ganglion cells innervating nasal mucosa was investigated using patch clamp electrophysiology. A guinea pig model of rhinitis was developed using intranasal challenge of capsaicin and hypertonic saline to elicit nasal secretory parasympathetic reflex responses, quantified using MRI. The inhibitory effect of SB-705498, duration of action and potency comparing oral versus intranasal route of administration were examined.

Key Results: SB-705498 concentration-dependently inhibited capsaicin-induced currents in isolated trigeminal ganglion cells (pIC50 7.2). In vivo, capsaicin ipsilateral nasal challenge (0.03-1 mM) elicited concentration-dependent increases in contralateral intranasal fluid secretion. Ten per cent hypertonic saline initiated a similar response. Atropine inhibited responses to either challenge. SB-705498 inhibited capsaicin-induced responses by ∼50% at 10 mg·kg⁻¹ (oral), non-micronized 10 mg·mL⁻¹ or 1 mg·mL⁻¹ micronized SB-705498 (intranasal) suspension. Ten milligram per millilitre intranasal SB-705498, dosed 24 h prior to capsaicin challenge produced a 52% reduction in secretory response. SB-705498 (10 mg·mL⁻¹, intranasal) inhibited 10% hypertonic saline responses by 70%.

Conclusions And Implications: The paper reports the development of a guinea pig model of rhinitis. SB-705498 inhibits capsaicin-induced trigeminal currents and capsaicin-induced contralateral nasal secretions via oral and intranasal routes; efficacy was optimized using particle-reduced SB-705498. We propose that TRPV1 is pivotal in initiating symptoms of rhinitis.
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http://dx.doi.org/10.1111/bph.12145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682706PMC
June 2013

Does weight-adjusted anti-tumour necrosis factor treatment favour obese patients with Crohn's disease?

Eur J Gastroenterol Hepatol 2013 May;25(5):543-9

St James's University Hospital, Leeds, UK.

Background: Adalimumab (ADA) is a subcutaneous anti-tumour necrosis factor (anti-TNF) agent, effective in inducing and maintaining remission in Crohn's disease (CD). Unlike Infliximab (IFX), ADA dosing is not weight adjusted and dose frequency is based on clinical response.

Aim: To determine whether obesity is a risk factor for early loss of response (LOR) to anti-TNF treatment and whether weight-adjusted anti-TNF treatment is favourable.

Materials And Methods: A hospital database of CD patients receiving anti-TNF treatment was analyzed retrospectively. The relationship between time to LOR and BMI was examined by Kaplan-Meier (KM) survival curves and a Cox proportional hazards model.

Results: ADA patients: Of the 54 patients (46 BMI<30 and 8 BMI≥30), KM estimation indicated a significantly shorter time to dose escalation in the BMI of at least 30 (χ=6.117, P=0.01). The Cox proportional hazards model showed that an increased hazard of LOR to ADA is related to increases in BMI (P=0.04). IFX patients: Of the 76 patients (62 BMI<30 and 14 BMI≥30), KM estimation showed that the differences in survival curves were not significant (χ=1.933, P=0.16) for the BMI groups. This was supported by the Cox proportional hazard model (P=0.36).

Conclusion: BMI appears to be important in predicting ADA efficacy (LOR) in CD. IFX appears to overcome this reduction of efficacy in obese patients. A prospective study evaluating the effect of weight on anti-TNF drug response and serum drug levels is warranted.
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http://dx.doi.org/10.1097/MEG.0b013e32835d1f15DOI Listing
May 2013

Results from the 2nd Scientific Workshop of the ECCO. I: Impact of mucosal healing on the course of inflammatory bowel disease.

J Crohns Colitis 2011 Oct 3;5(5):477-83. Epub 2011 Aug 3.

INSERM U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy, Université Henri Poincaré 1, Vandoeuvre-lès-Nancy, France.

Over the past years, mucosal healing has emerged as a major therapeutic goal in clinical trials in inflammatory bowel diseases. Accumulating evidence indicates that mucosal healing may change the natural course of the disease by decreasing the need for surgery and reducing hospitalization rates in both ulcerative colitis and Crohn's disease. Mucosal healing may also prevent the development of long-term disease complications, such as bowel damage in Crohn's disease and colorectal cancer in ulcerative colitis. Histologic healing may be the ultimate therapeutic goal in ulcerative colitis, whereas its impact on the course of Crohn's disease is unknown. Complete mucosal healing may be required before considering drug withdrawal. Targeting early Crohn's disease is more effective than approaches aimed at healing mucosa in longstanding disease. Several questions remain to be answered: should mucosal healing be systematically used in clinical practice? Should we optimize therapies to achieve mucosal healing? What is the degree of intestinal healing that is required to change the disease course? Large prospective studies addressing these issues are needed.
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http://dx.doi.org/10.1016/j.crohns.2011.06.009DOI Listing
October 2011

Preferable colonic investigations for isolated abdominal pain.

South Med J 2011 Mar;104(3):170-3

Department of Gastroenterology Manchester Royal Infirmary, Manchester, United Kingdom.

Objectives: Isolated abdominal pain is seen as a poor indication for colonic investigations. The yield of serious pathology detected by optical colonoscopy (OC) has differed greatly in published series. This study aims to establish the yield of colonic investigations for isolated abdominal pain.

Methods: A retrospective analysis of the endoscopy database was undertaken on all OCs performed from 2000 to 2008. The yield of OCs for detection of pathology (polyps, cancers, and inflammatory bowel disease) was compared for the symptoms of abdominal pain, chronic diarrhea, or anemia. Data on computed tomographic colonographies (CTC), performed for isolated abdominal pain in 2008, were used to compare the yield of CTCs and OCs.

Results: Of the 8564 OCs and 525 CTCs performed, 5.4% and 8.2% were undertaken for isolated abdominal pain, respectively. The yield of OCs for overall pathology detection was not significantly different for abdominal pain (23.87%), compared to other indications (20.34-24.85%). The yield of pathology detection was not significantly different for CTC (20.93%) and OC. Colonic polyps were the most common pathology (OC 16.05%, CTC 18.6%).

Conclusion: Colonic investigations undertaken for isolated abdominal pain had a high yield of incidental colonic pathology. The detection of polyps could be beneficial, but it does not explain the symptoms. CTC offers a less invasive way of detecting colonic pathology in such patients, while maintaining the same yield. If CTC is used as a first line of investigation, it could spare 75% of patients the colonoscopy procedure.
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http://dx.doi.org/10.1097/SMJ.0b013e318200c38bDOI Listing
March 2011

Natural history of azathioprine-associated lymphopenia in inflammatory bowel disease patients: a prospective observational study.

Eur J Gastroenterol Hepatol 2011 Feb;23(2):153-8

Department of Gastroenterology, Central Manchester University Hospitals NHS Foundation, University of Manchester, Manchester, UK.

Introduction: Azathioprine (AZA) is commonly used in inflammatory bowel disease (IBD) patients. Lymphopenia is a recognized effect of this treatment, but lymphopenia-related complications in IBD patients have not been widely reported. The incidence and progression of AZA-induced lymphopenia in IBD patients is not well described. There is no consensus on its optimal management in this group.

Aims And Methods: We assessed the incidence and progression of lymphopenia and its related complications in a cohort of IBD patients over a 14-month period in two large tertiary gastroenterology units. Analysis of prospectively collected data was performed.

Results: Fifty-two patients were studied prospectively with a median age of 34 years. Eighteen patients (34.6%) developed lymphopenia (<1.0×10(9)/l) during the course of treatment and 10 of them had severe lymphopenia (<0.6×10(9)/l). Lymphopenia lasted on average 85.4 days and spontaneously resolved in 13 patients. No lymphopenia related-complications were documented. Patients treated with steroids had a significantly higher rate of lymphopenia (83.3 vs. 44.1%, P=0.0083).

Conclusion: Lymphopenia is common among IBD patients treated with AZA. However, it did not seem to be associated with a higher risk of opportunistic infections and spontaneously resolved in the majority of cases.
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http://dx.doi.org/10.1097/MEG.0b013e32834233a2DOI Listing
February 2011

Replication and meta-analysis of 13,000 cases defines the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn's disease.

Can J Gastroenterol 2010 May;24(5):297-302

Department of Medical Genetics, Manchester Academic Health, Manchester, United Kingdom.

Background/objective: Variants in the interleukin-23 receptor (IL23R) and the autophagy-related 16-like 1 (ATG16L1) genes have been associated with an increased risk of Crohn's disease (CD). Both genes were identified through genome-wide association scans and subsequent studies have validated these associations. To assess the effect size of these variants, an independent case-control association study and meta-analysis were performed.

Methods: British Caucasian subjects with inflammatory bowel disease (n=500) and 877 ethnically matched controls were genotyped for the disease-associated variants in IL23R and ATG16L1. In addition, meta-analyses of 12,991 patients and 14,598 controls, and 11,909 patients and 15,798 controls, were conducted on independently published data for the associations between IL23R and ATG16L1 variants and CD, respectively.

Results: In the present cohort, both susceptibility variants showed highly significant associations, including IL23R (rs11209026, P=0.0006; OR 0.37; 95% CI 0.21 to 0.67) and ATG16L1 (rs2241880, P=0.0017; OR 1.36; 95% CI 1.12 to 1.66). The meta-analysis based on the random effects model showed similar combined effects for rs11209026 (n=26, OR 0.41; 95% CI 0.37 to 0.46) and rs2241880 (n=25, OR 1.33; 95% CI 1.28 to 1.39). There was no statistically significant gene-gene interaction between caspase recruitment domain (CARD15) variants and the IL23R or ATG16L1 polymorphisms (P=0.44 and P=0.24, respectively).

Conclusion: The present cohort and meta-analysis provides strong evidence that, in addition to CARD15, polymorphisms in both IL23R and ATG16L1 alter susceptibility to CD and that these effects are consistent across all populations of European ancestry; however, only ATG16L1 is relevant to inflammatory bowel disease in the Asian population.
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http://dx.doi.org/10.1155/2010/480458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886570PMC
May 2010
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