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A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

Suchowerska, A.K. (author), Stokman, G. (author), Palmer, J.T. (author), Coghlan, P.A. (author), Pieterman, E.J. (author), Keijzer, N. (author), Lambert, G. (author), Chemello, K. (author), Jaafar, A.K. (author), Parmar, J. (author), Yan, L. (author), Tong, Y. (author), Mu, L. (author), Princen, H.M.G. (author), Bonnar, J. (author), Evison, B.J. (author)

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to...

article 2022

document

REACH, non-testing approaches and the urgent need for a change in mind set

Schaafsma, G. (author), Kroese, E.D. (author), Tielemans, E.L.J.P. (author), van de Sandt, J.J.M. (author), van Leeuwen, C.J. (author), TNO Kwaliteit van Leven (author)

The objectives of REACH cannot be achieved under the current risk assessment approach. A change in mind set among all the relevant stakeholders is needed: risk assessment should move away from a labor-intensive and animal-consuming approach to intelligent and pragmatic testing, by combining exposure and hazard data effectively and trying to...

article 2009

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Nonclinical testing of vaccines: Report from a workshop

van der Laan, J.W. (author), Forster, R. (author), Ledwith, B. (author), Gruber, M. (author), Gould, S. (author), Segal, L. (author), Penninks, A. (author), TNO Kwaliteit van Leven (author)

Vaccine research and development is a heterogeneous and intensely active area, encompassing the development of many different kinds of novel preventive and therapeutic vaccines (eg, against infectious, allergic, and autoimmune diseases, cancer, etc). Included in this is the development of different types of vaccines (eg, DNA vaccines, novel...

article 2009

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The evaluation of the immunomodulating properties of ERA-63 a pharmaceutical with estrogenic activity

Janssen, G.B. (author), Penninks, A.H. (author), Knippels, L.M.J. (author), van Zijverden, M. (author), Spanhaak, S. (author), TNO Kwaliteit van Leven (author)

This paper describes studies performed with ERA-63 a low molecular weight pharmaceutical with intended immunomodulatory effects. Since this compound was also known to have estrogenic activity a non-conventional approach was taken in order to differentiate between estrogenic and non-estrogenic-induced immunomodulatory effects. EE was included not...

article 2008

document

Rescuing drug discovery: In vivo systems pathology and systems pharmacology

van der Greef, J. (author), McBurney, R.N. (author), TNO Kwaliteit van Leven (author)

The pharmaceutical industry is currently beleaguered by close scrutiny from the financial community, regulators and the general public. Productivity, in terms of new drug approvals, has generally been falling for almost a decade and the safety of a number of highly successful drugs has recently been brought into question. Here, we discuss...

article 2005

document

Biological evaluation of Tyr6 and Ser7 modified drosocin analogues

de Visser, P.C. (author), van Hooft, P.A.V. (author), de Vries, A.-M. (author), de Jong, A. (author), van der Marel, G.A. (author), Overkleeft, H.S. (author), Noort, D. (author), TNO Defensie en Veiligheid (author)

An array of analogues of the cationic antimicrobial peptide drosocin was synthesized containing substitutions of Tyr6 and Ser7 in order to increase the proteolytic stability. Stabilizing the N-terminus with unnatural amino acids increased the serum stability of analogues by almost a factor 30 over an 8 h period. © 2005 Elsevier Ltd. All rights...

article 2005

document

Food allergy: What do we learn from animal models?

Knippels, L.M.J. (author), van Wijk, F. (author), Penninks, A.H. (author), TNO Voeding (author)

Purpose of review This review summarizes selected articles on animal models of food allergy published in 2003. The research areas that are covered include mechanistic studies, the search for new therapies, as well as screening models for hazard identification of potential allergens. Recent findings Novel treatment options of both prevention and...

article 2004

document

Modulating angiogenesis: The yin and the yang in ginseng

Sengupta, S. (author), Toh, S.A. (author), Sellers, L.A. (author), Skepper, J.N. (author), Koolwijk, P. (author), Leung, H.W. (author), Yeung, H.W. (author), Wong, R.N.S. (author), Sasisekharan, R. (author), Fan, T.P.D. (author)

Background-Ginseng is a commonly used nutraceutical. Intriguingly, existing literature reports both wound-healing and antitumor effects of ginseng extract through opposing activities on the vascular system. To elucidate this perplexity, we merged a chemical fingerprinting approach with a deconstructional study of the effects of pure molecules...

article 2004

document

Synthesis and antimicrobial evaluation of farnesyl diphosphate mimetics

Fairlamb, I.J.S. (author), Dickinson, J.M. (author), O'Connor, R. (author), Cohen, L.H. (author), van Thiel, C.F. (author)

The synthesis and first antimicrobial evaluation of farnesyl diphosphate mimetics are described. Several analogues (10, 12, 13, and 20) are inhibitors of Candida albicans, Shizosaccharomyces pombe, and Saccharomyces cerevisiae. The activities of analogues 10, 12, and 13, which contain a ω-phenyl moiety and a diphosphate isostere, are not...

article 2003

document

Role of metallothionein in cisplatin sensitivity of germ-cell tumours

Meijer, C. (author), Timmer, A. (author), de Vries, E.G.E. (author), Groten, J.P. (author), Knol, A. (author), Zwart, N. (author), Dam, W.A. (author), Sleijfer, D.Th. (author), Mulder, N.H. (author)

Cisplatin (CDDP) is an extremely active drug in the treatment of germ- cell tumours. Earlier, we found an unexpected inverse correlation between the total amount of sulfhydryl groups and CDDP sensitivity in a panel of 3 human germ-cell tumour and 3 colon-carcinoma cell lines. Major components of the sulfhydryl groups are glutathione and...

article 2000

document

Short-term tests of estrogenic potential of plant stanols and plant stanol esters

Turnbull, D. (author), Frankos, V.H. (author), Leeman, W.R. (author), Jonker, D. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

To test for potential estrogenic activity of plant stanols and plant stanol esters, two short-term tests were performed. These were the E-screen test, which measures a substance's ability to induce proliferation of estrogen-responsive human breast adenocarcinoma (MCF-7) cells in culture, and an in vivo test, which measures uterotrophic activity...

article 1999

document

Pharmacodynamics of cisplatin in human head and neck cancer: correlation between platinum content, DNA adduct levels and drug sensitivity in vitro and in vivo

Centraal Instituut voor Voedingsonderzoek TNO TNO Voeding (author), Welters, M.J.P. (author), Fichtinger-Schepman, A.M.J. (author), Baan, R.A. (author), Jacobs-Bergmans, A.J. (author), Kegel, A. (author), van der Vijgh, W.J.F. (author), Braakhuis, B.J.M. (author)

Total platinum contents and cisplatin-DNA adduct levels were determined in vivo in xenografted tumour tissues in mice and in vitro in cultured tumour cells of head and neck squamous cell carcinoma (HNSCC), and correlated with sensitivity to cisplatin. In vivo, a panel of five HNSCC tumour lines growing as xenografts in nude mice was used. In...

article 1999

document

Apolipoprotein E*3-Leiden transgenic mice mode for hypolipidaemic drugs

Gaubius Instituut TNO (author), van Vlijmen, B.J.M. (author), Pearce, N.J. (author), Bergö, M. (author), Staels, B. (author), Yates, J.W. (author), Gribble, A.D. (author), Bond, B.C. (author), Hofker, M.H. (author), Havekes, L.M. (author), Groot, P.H.E. (author)

Apolipoprotein (APO) E*3-Leiden mice with impaired chylomicron and VLDL (very low density lipoprotein) remnant metabolism display hyperlipidaemia and atherosclerosis. In the present study, these mice were used for testing the hypolipidaemic effect of two marketed agents, lovastatin (CAS 75330-75-5) and gemfibrozil (CAS 25812-30-0) as well as a...

article 1998

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Inhibiting interleukin-1 and tumor necrosis factor-α does not reduce induction of plasminogen activator inhibitor type-1 by endotoxin in rats in vivo

Emeis, J.E. (author), Hoekzema, R. (author), de Vos, A.F. (author), TNO Preventie en Gezondheid (author)

In experimental animals and humans, intravenous (IV) injection of endotoxin induces large increases in circulating plasminogen activator inhibitor type-1 (PAI-1), a major inhibitor of blood fibrinolysis. A similar increase is seen after the injection of interleukin-1 (IL-1) or of tumor necrosis factor-α (TNF-α), suggesting that these cytokines...

article 1995

document

Acetyldinaline: A new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells - Preclinical studies in a relevant rat model for human acute myelocytic leukemia

El-Beltagi, H.M. (author), Martens, A.C.M. (author), Lelieveld, P. (author), Haroun, E.A. (author), Hagenbeek, A. (author), Instituut voor Toegepaste Radiobiologie en Immunologie TNO (author)

Acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'- aminophenyl)-benzamide] is the acetylated derivative form of the original compound Dinaline (GOE 1734; PD 104 208). The efficacy and toxicity of Acetyldinaline for remission-induction treatment of leukemia were evaluated and compared with those observed in previous studies of...

article 1993

document

Short-term tests in the framework of carcinogen risk assessment to man

Kroes, R. (author), Instituut CIVO-Toxicologie en voeding TNO (author)

Short-term tests designed to detect possible carcinogenicity have been extensively refined during the last years. Presently, many more or less simple and convenient systems are available to detect mutations, chromosome effects, DNA damage, and malignant transformation. Although their relevance to carcinogenicity is often reasonably good,...

article 1983

document

Tissue culture and neurotoxicology

Hooisma, J. (author), Medisch Biologisch Laboratorium TNO (author)

Application of tissue culture in neurotoxicology may serve two purposes. First, they may be used to unravel the mechanism of action of neurotoxic compounds and secondly, they may be used for the screening of neurotoxic agents. Studies belonging to the first group can be subdivided into those aiming at the replication of neurotoxic processes in...

article 1982

document

Antidotes to organophosphate poisoning. 2. Thiadiazole-5-carboxaldoximes

Benschop, H.P. (author), van den Berg, G.R. (author), van Hooidonk, C. (author), de Jong, L.P.A. (author), Kientz, C.E. (author), Berends, F. (author), Kepner, L.A. (author), Meeter, E. (author), Visser, R.P.L.S. (author), Medisch Biologisch Laboratorium TNO (author)

Three new nonquaternary oximes have been evaluated with respect to their antidotal activities against organophosphate poisoning. The oximes 1,2,3-thiadiazole-5-carboxaldoxime (1, pKa = 7.6), 2-methyl-1,3,4-thiadiazole-5-carboxaldoxime (2, pKa = 8.4), and 3-methyl-1,2,4-thiadiazole-5-carboxaldoxime (3, pKa = 7.0) were prepared in yields of 56, 24...

article 1979

document

Report of a workshop on bacterial in vitro mutagenicity test systems

Mattern, I.E. (author), Greim, H. (author), Medisch Biologisch Laboratorium TNO (author)

Bacterial systems for the screening of chemical substances for mutagenic potential are receiving widespread attention. Now that many laboratories have introduced these test systems and a large number of substances has been tested, discrepancies in the results have become apparent. To discuss this problem, a workshop was organized at Neuherberg ...

article 1978

document

Mutagenicity testing of urine from vinylchloride (VCM) treated rats using the salmonella test system

Mattern, I.E. (author), van der Zwaan, W.B. (author), Willems, M.J. (author), Medisch Biologisch Laboratorium TNO (author)

Chemicals/CAS: soybean oil, 8001-22-7; vinyl chloride, 75-01-4

article 1977