Oxagen (United Kingdom)

Eosinophilic esophagitis (EoE) is a chronic, Th2-type inflammatory disease. Chemoattractant receptor-homologous molecule on Th2 cells (CRTH2) is a prostaglandin D(2) (PGD(2)) receptor, expressed by Th2 cells and other inflammatory cells, including eosinophils and basophils, that mediates chemotaxis and activation. OC000459 is a selective CRTH2 antagonist and would be expected to suppress eosinophilic tissue inflammation. The purpose of this study was to evaluate the efficacy and safety of an OC000459 monotherapy in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE. In this randomized, double-blind, placebo-controlled trial, 26 adult patients (m/f = 22/4; mean age 41 years, range 22-69 years) with active EoE, dependent or resistant to corticosteroids, were treated either with 100 mg OC000459 (n = 14) or placebo (n = 12) twice daily. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, and via biomarkers. The primary end point was the reduction in esophageal eosinophil infiltration. After an 8-week OC000459 treatment, the esophageal eosinophil load decreased significantly, from 114.83 to 73.26 eosinophils per high-power field [(eos/hpf), P = 0.0256], whereas no reduction was observed with placebo (102.80-99.47 eos/hpf, P = 0.870). With OC000459, the physician's global assessment of disease activity improved from 7.13 to 5.18 (P = 0.035). OC000459 likewise reduced extracellular deposits of eosinophil peroxidase and tenascin C, the effects not seen with placebo. No serious adverse events were observed. An 8-week treatment with the CRTH2-antagonist, OC000459, exerts modest, but significant, anti-eosinophil and beneficial clinical effects in adult patients with active, corticosteroid-dependent or corticosteroid-refractory EoE and is well tolerated.

Prostaglandin H1 (PGH1) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as “anti-inflammatory”. Herein we present evidence that PGH1 is a potent activator of the pro-inflammatory PGD2 receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca2+ flux studies reveal that PGH1 activates CRTH2 as PGH2, PGD2 or PGD1 do. The PGH1 precursor DGLA and the other PGH1 metabolites did not display such effect. PGH1 specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH1 is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH1 mediates migration of and Ca2+ flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH1 as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase.

Prostaglandin D2 (PGD2) acting at the CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells) has been linked with a variety of allergic and other inflammatory diseases. We describe a family of indole-1-sulfonyl-3-acetic acids that are potent and selective CRTH2 antagonists that possess good oral bioavailability. The compounds may serve as novel starting points for the development of treatments of inflammatory disease such as asthma, allergic rhinitis, and atopic dermatitis.

Type 1 diabetes susceptibility at the IDDM2 locus was previously mapped to a variable number tandem repeat (VNTR) 5' of the insulin gene (INS). However, the observation of associated markers outside a 4.1-kb interval, previously considered to define the limits of IDDM2 association, raised the possibility that the VNTR association might result from linkage disequilibrium (LD) with an unknown polymorphism. We therefore identified a total of 177 polymorphisms and obtained genotypes for 75 of these in up to 434 pedigrees. We found that, whereas disease susceptibility did map to within the 4.1-kb region, there were two equally likely candidates for the causal variant, -23HphI and +1140A/C, in addition to the VNTR. Further analyses in 2,960 pedigrees did not support the difference in association between VNTR lineages that had previously enabled the exclusion of these two polymorphisms. Therefore, we were unable to rule out -23HphI and +1140A/C having an etiological effect. Our mapping results using robust regression methods show how precisely a variant for a common disease can be mapped, even within a region of strong LD, and specifically that IDDM2 maps to one or more of three common variants in a approximately 2-kb region of chromosome 11p15.

Abstract A new method (called New Relative Length) was developed for comparison of chromosome size when both paired and unpaired chromosomes are present. All chromosomes were used in the calculation. A method of graphical display of karyotype data (called a Karyotype Graph), plotting New Relative Length on the vertical axis and arm ratio on the horizontal axis was used to indicate sampling error, to pair chromosomes and to match similar chromosomes in related species. Terms for Chromosome Size were also defined namely Small, Medium or Large depending on New Relative Length as a proportion of total chromosome length. These terms could also be used to compare chromosomes within species and between related species.

Conference Abstract| August 01 2001 The Study of the Ibd Susceptibility Genes on Chromosome 5 and Chromosome 19 Hong Li Jin; Hong Li Jin 1 Gastroenterology Unit, Gibson Laboratories, Radcliffe Infirmary, University of Oxford, OXFORD OX2 6HE Search for other works by this author on: This Site PubMed Google Scholar B Dechairo; B Dechairo 2 Oxagen Ltd, Milton Park, Oxon OX14 4RY Search for other works by this author on: This Site PubMed Google Scholar F Williams; F Williams 2 Oxagen Ltd, Milton Park, Oxon OX14 4RY Search for other works by this author on: This Site PubMed Google Scholar NJ Lench; NJ Lench 2 Oxagen Ltd, Milton Park, Oxon OX14 4RY Search for other works by this author on: This Site PubMed Google Scholar DP Jewell DP Jewell 1 Gastroenterology Unit, Gibson Laboratories, Radcliffe Infirmary, University of Oxford, OXFORD OX2 6HE Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (2001) 101 (s45): 12P. https://doi.org/10.1042/cs101012P Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation Hong Li Jin, B Dechairo, F Williams, NJ Lench, DP Jewell; The Study of the Ibd Susceptibility Genes on Chromosome 5 and Chromosome 19. Clin Sci (Lond) 1 August 2001; 101 (s45): 12P. doi: https://doi.org/10.1042/cs101012P Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 2001 The Biochemical Society and the Medical Research Society2001 Article PDF first page preview Close Modal You do not currently have access to this content.

This paper (i) reviews the current clinical and molecular genetic data which strongly suggest that endometriosis has a genetic basis; (ii) outlines the general principles of affected-sib pair analysis; and (iii) describes the Oxford Endometriosis Gene (OXEGENE) Study which aims, using a positional cloning approach, to identify susceptibility genes involved in the development of the disease.

Several panels are available for puchase, and this unit provides update information on the use of the three commercially available panels and on the interpretation of mapping results using the Internet. Radiation hybrid panels continue to serve as integral biological reagents in physical mapping projects and positional cloning.