Schering Plough Research Institute

Oss, Netherlands

Schering Plough Research Institute

Oss, Netherlands

Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co. merged with Schering-Plough with the new company taking the name of Merck & Co.Schering-Plough manufactured several pharmaceutical drugs, the most well-known of which were the allergy drugs Claritin and Clarinex, an anti-cholesterol drug Vytorin, and a brain tumor drug Temodar. These are now available from Merck & Co.Schering Plough also owned and operated the major foot care brand name Dr. Scholl's and the skin care line Coppertone. These also became a part of the new company.As of June 2005, Schering-Plough had 1.4% market share in the U.S., placing it seventeenth in the top twenty pharmaceutical corporations by sales compiled by IMS Health.Schering-Plough was a full member of the European Federation of Pharmaceutical Industries and Associations , a membership which is also maintained by the new Merck. Wikipedia.

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Bovee T.F.H.,RIKILT Institute of Food Safety | Thevis M.,German Sport University Cologne | Hamers A.R.M.,RIKILT Institute of Food Safety | Peijnenburg A.A.C.M.,RIKILT Institute of Food Safety | And 3 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2010

Selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs) are compounds that activate their cognate receptor in particular target tissues without affecting other organs. Many of these compounds will find their use in therapeutic treatments. However, they also will have a high potential for misuse in veterinary practice and the sporting world. Here we demonstrate that yeast estrogen and androgen bioassays can be used to detect SERMs and SARMs, and are also useful screening tools to investigate their mode of action. Six steroidal 11β-substituents of E2 (SERMs) and some arylpropionamide- and quinoline-based SARMs were tested. In addition, 7 compounds previously tested on AR agonism and determined as inactive in the yeast androgen bioassay, while QSAR modelling revealed strong binding to the human androgen receptor, are now shown to act as AR antagonists. © 2009 Elsevier Ltd. All rights reserved.

Westerink W.M.A.,Schering Plough Research Institute | Stevenson J.C.R.,Schering Plough Research Institute | Horbach G.J.,Schering Plough Research Institute | Schoonen W.G.E.J.,Schering Plough Research Institute
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2010

Four different mechanism-based high-throughput luciferase-reporter assays were developed in human HepG2 cells, which contain phase I and II metabolic activity and a functionally active p53 protein. The promoter regions of RAD51C and Cystatin A, as well as the responsive element of the p53 protein, were selected for the generation of the genotoxicity reporter assays. Moreover, a luciferase-based reporter assay was generated that measures the activation of the Nrf2 oxidative stress pathway. Validation with respect to the ECVAM compound list [D. Kirkland, P. Kasper, L. Muller, R. Corvi, G. Speit, Recommended lists of genotoxic and non-genotoxic chemicals for assessment of the performance of new or improved genotoxicity tests: a follow-up to an ECVAM workshop, Mutat. Res. 653 (2008) 99-108] resulted in an overall sensitivity of the HepG2 genotoxicity reporter assays for genotoxicity of 85% (17/20). The specificity and predictivity were high with 81% (34/42) and 82% (51/62), respectively. Various compounds had a positive score although metabolic activation was needed. The HepG2 reporter data were also compared with the available data on bacterial mutagenicity (Ames test), in vitro clastogenicity and in vivo clastogenicity for an additional set of 192 compounds. The predictivity for mutagenicity results was 74% (sensitivity, 61%, 30/49; specificity, 80%, 77/96) and for in vitro clastogenicity 59% (sensitivity, 45%, 35/78; specificity 83%, 38/46). The correlation between results from the HepG2 genotoxicity reporter assays and in vivo clastogenicity was much higher with 77% (sensitivity, 74%, 28/38; specificity 81%, 26/32). Results from the Nrf2 reporter assay showed that a large number of genotoxic compounds activated the Nrf2 oxidative stress pathway. In conclusion, four high-throughput mechanism-based reporter assays in the HepG2 cell line were developed, which can be applied for screening in the early research phase of drug development. The use of these assays in combination with the previously validated Vitotox and RadarScreen assays will certainly reduce the attrition rate due to genotoxicity in the developmental phase of drug development. © 2009 Elsevier B.V. All rights reserved.

Bonger K.M.,Leiden University | Kapoerchan V.V.,Leiden University | Grotenbreg G.M.,Leiden University | Van Koppen C.J.,Schering Plough Research Institute | And 3 more authors.
Organic and Biomolecular Chemistry | Year: 2010

Oligoprolines (OPs) are used as rigid backbone scaffolds for the design of oligomeric ligands that target specific G protein-coupled receptors. The OPs were designed to vary in length, the position and number of the ligand-functionalized residues incorporated. For all synthesized compounds a typical PP type II helix was evidenced by circular dichroism indicating that decoration of the helix with large ligands did not affect the helical conformation. Pharmacological evaluation revealed that oligomerization of an agonist with the use of an oligoproline scaffold showed an increase in potency when compared to the monomeric counterparts. © 2010 The Royal Society of Chemistry.

Van Raalte D.H.,VU University Amsterdam | Nofrate V.,National Research Council Italy | Bunck M.C.,VU University Amsterdam | Van Iersel T.,Xendo Drug Development | And 6 more authors.
European Journal of Endocrinology | Year: 2010

Objective: Glucocorticoids (GCs), such as prednisolone, are associated with adverse metabolic effects, including glucose intolerance and diabetes. In contrast to the well known GC-induced insulin resistance, the effects of GCs on β-cell function are less well established. We assessed the acute and short-term effects of prednisolone treatment on β-cell function in healthy men. Research design and methods: A randomised, double-blind, placebo-controlled trial consisting of two protocols was conducted. In protocol 1 (n = 6), placebo and a single dose of 75 mg of prednisolone were administered. In protocol 2 (n = 23), participants received 30 mg of prednisolone daily or placebo for 15 days. Both empirical and model-based parameters of β-cell function were calculated from glucose, insulin and C-peptide concentrations obtained during standardised meal tests before and during prednisolone treatment (protocols 1 and 2), and 1 day after cessation of treatment (protocol 2). Results: Seventy-five milligrams of prednisolone acutely increased the area under the postprandial glucose curve (AUCgluc; P = 0.005), and inhibited several parameters of β-cell function, including AUCc-pep/ AUCgluc ratio (P = 0.004), insulinogenic index (P = 0.007), glucose sensitivity (P = 0.02) and potentiation factor ratio (PFR; PZ0.04). A 15-day treatment with prednisolone increased AUCgluc (P < 0.001), despite augmented C-peptide secretion (P = 0.05). β-cell function parameters were impaired, including the fasting insulin secretory tone (P = 0.02) and PFR (P = 0.007). Conclusions: Acute and short-term exposure to prednisolone impairs different aspects of β-cell function, which contribute to its diabetogenic effects. © 2010 European Society of Endocrinology.

Fatemi H.M.,Universitair Ziekenhuis Brussel | Oberye J.,Schering Plough Research Institute | Popovic-Todorovic B.,Universitair Ziekenhuis Brussel | Witjes H.,Schering Plough Research Institute | And 2 more authors.
Fertility and Sterility | Year: 2010

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 μg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation. Copyright © 2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

Dulos J.,Schering Plough Research Institute | Vijn P.,Schering Plough Research Institute | van Doorn C.,Schering Plough Research Institute | Hofstra C.L.,Schering Plough Research Institute | And 4 more authors.
Arthritis Research and Therapy | Year: 2010

Introduction: The immune modulatory role of estrogens in inflammation is complex. Both pro- and anti-inflammatory effects of estrogens have been described. Estrogens bind both estrogen receptor (ER)α and β. The contribution of ERα and ERβ to ER-mediated immune modulation was studied in delayed type hypersensitivity (DTH) and in experimental arthritis. Methods: ER-mediated suppression of rat adjuvant arthritis (AA) was studied using ethinyl-estradiol (EE) and a selective ERβ agonist (ERB-79). Arthritis was followed for 2 weeks. Next, effects of ER agonists (ethinyl-estradiol, an ERα selective agonist (ERA-63) and a selective ERβ agonist (ERB-79) on the development of a tetanus toxoid (TT)-specific delayed type hypersensitivity response in wild type (WT) and in ERα - or ERβ-deficient mice were investigated. Finally, EE and ERA-63 were tested for their immune modulating potential in established collagen induced arthritis in DBA/1J mice. Arthritis was followed for three weeks. Joint pathology was examined by histology and radiology. Local synovial cytokine production was analyzed using Luminex technology. Sera were assessed for COMP as a biomarker of cartilage destruction.Results: EE was found to suppress clinical signs and symptoms in rat AA. The selective ERβ agonist ERB-79 had no effect on arthritis symptoms in this model. In the TT-specific DTH model, EE and the selective ERα agonist ERA-63 suppressed the TT-specific swelling response in WT and ERβKO mice but not in ERαKO mice. As seen in the AA model, the selective ERβ agonist ERB-79 did not suppress inflammation. Treatment with EE or ERA-63 suppressed clinical signs in collagen induced arthritis (CIA) in WT mice. This was associated with reduced inflammatory infiltrates and decreased levels of proinflammatory cytokines in CIA joints.Conclusions: ERα, but not ERβ, is key in ER-mediated suppression of experimental arthritis. It remains to be investigated how these findings translate to human autoimmune disease. © 2010 Dulos et al.; licensee BioMed Central Ltd.

Mentink A.,University of Twente | Hulsman M.,Technical University of Delft | Groen N.,University of Twente | Licht R.,University of Twente | And 8 more authors.
Biomaterials | Year: 2013

Mesenchymal stromal cells (hMSCs) are advancing into the clinic but the therapeutic efficacy of hMSCs faces the problem of donor variability. In bone tissue engineering, no reliable markers have been identified which are able to predict the bone-forming capacity of hMSCs prior to implantation. To this end, we isolated hMSCs from 62 donors and characterized systematically their in vitro lineage differentiation capacity, gene expression signature and in vivo capacity for ectopic bone formation. Our data confirms the large variability of in vitro differentiation capacity which did not correlate with in vivo ectopic bone formation. Using DNA microarray analysis of early passage hMSCs we identified a diagnostic bone-forming classifier. In fact, a single gene, CADM1, strongly correlated with the bone-forming capacity of hMSCs and could be used as a reliable in vitro diagnostic marker. Furthermore, data mining of genes expressed correlating with in vivo bone formation represented involvement in neurogenic processes and Wnt signaling. We will apply our data set to predict therapeutic efficacy of hMSCs and to gain novel insight in the process of bone regeneration. Our bio-informatics driven approach may be used in other fields of cell therapy to establish diagnostic markers for clinical efficacy. © 2013 Elsevier Ltd.

Doody K.,Center for Assisted Reproduction | Devroey P.,Universitair Ziekenhuis | Gordon K.,Schering | Witjes H.,Schering Plough Research Institute | Mannaerts B.,Schering Plough Research Institute
Reproductive BioMedicine Online | Year: 2010

The possible relationship between endogenous LH concentrations and clinical outcome was evaluated in 750 patients treated with a standardized gonadotrophin-releasing hormone (GnRH) antagonist and recombinant FSH (rFSH)-only protocol. Serum LH concentrations were measured during stimulation by a central laboratory and patients were stratified into quantiles of P75. The P25 values were 3.38 IU/1, 0.93 IU/1, and 0.91 IU/1 on stimulation days 1, 5, and 8, respectively. The ongoing pregnancy rates per started cycle of patients within the P75 subsets and ranged in the various subsets between 35.0% and 39.5%. In keeping with previous, smaller studies, these findings demonstrate that in good prognosis, non-obese patients endogenous LH in a GnRH antagonist protocol is able to support treatment with rFSH only. © 2009, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Vottero E.,VU University Amsterdam | Rea V.,VU University Amsterdam | Lastdrager J.,VU University Amsterdam | Honing M.,Schering Plough Research Institute | And 2 more authors.
Journal of Biological Inorganic Chemistry | Year: 2011

CYP102A1, originating from Bacillus megaterium, is a highly active enzyme which has attracted much attention because of its potential applicability as a biocatalyst for oxidative reactions. Previously we developed drug-metabolizing mutant CYP102A1 M11 by a combination of site-directed and random mutagenesis. CYP102A1 M11 contains eight mutations, when compared with wild-type CYP102A1, and is able to produce human-relevant metabolites of several pharmaceuticals. In this study, active-site residue 87 of drug-metabolizing mutant CYP102A1 M11 was mutated to all possible natural amino acids to investigate its role in substrate selectivity and regioselectivity. With alkoxyresorufins as substrates, large differences in substrate selectivities and coupling efficiencies were found, dependent on the nature of residue 87. For all combinations of alkoxyresorufins and mutants, extremely fast rates of NADPH oxidation were observed (up to 6,000 min -1). However, the coupling efficiencies were extremely low: even for the substrates showing the highest rates of O-dealkylation, coupling efficiencies were lower than 1%. With testosterone as the substrate, all mutants were able to produce three hydroxytestosterone metabolites, although with different activities and with remarkably different product ratios. The results show that the nature of the amino acid at position 87 has a strong effect on activity and regioselectivity in the drug-metabolizing mutant CYP102A1 M11. Because of the wide substrate selectivity of CYP102A1 M11 when compared with wild-type CYP102A1, this panel of mutants will be useful both as biocatalysts for metabolite production and as model proteins for mechanistic studies on the function of P450s in general. © 2011 The Author(s).

Verkaar F.,Schering Plough Research Institute | Verkaar F.,Maastricht University | Blankesteijn W.M.,Maastricht University | Smits J.F.M.,Maastricht University | Zaman G.J.R.,Schering Plough Research Institute
FASEB Journal | Year: 2010

Wnt/β-catenin signaling is an important regulator of cell polarity, proliferation, and stem cell maintenance during development and adulthood. Wnt proteins induce the nuclear accumulation of β-catenin, which regulates the expression of Wnt-responsive genes through association with TCF/LEF transcription factors. Aberrant Wnt/β-catenin signaling has been implicated in a plethora of pathologies and, most notably, underlies initiation and expansion of several cancers. Here, we apply enzyme fragment complementation to measure the nuclear accumulation of β-catenin. β-Catenin was tagged with a peptide fragment of β-galactosidase and transfected into cells expressing a corresponding deletion mutant of the enzyme exclusively in the nucleus. Stimulation of the cells with recombinant Wnt-3a restored β-galactosidase activity in a dose-dependent manner with nanomolar potency. Using the assay, we confirmed that Wnt-5a represses β-catenin-driven reporter gene activity downstream of nuclear entry of β-catenin. In addition, we tested a library of >2000 synthetic chemical compounds for their ability to induce β-catenin nuclear accumulation. The immunosuppressive protein kinase C inhibitor sotrastaurin (AEB-071) was identified as an activator of Wnt/β-catenin signaling at micromolar concentrations. It was confirmed that the compound stabilizes endogenous β-catenin protein and can induce TCF/LEF-dependent gene transcription. Subsequent biochemical profiling of >200 kinases revealed both isoforms of glycogen synthase kinase 3, as previously unappreciated targets of sotrastaurin. We show that the β-catenin nuclear accumulation assay contributes to our knowledge of molecular interactions within the Wnt/β-catenin pathway and can be used to find new therapeutics targeting Wnt/β-catenin signaling. © FASEB.

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