Angiogenesis: An improved in vitro biological system and automated image-based workflow to aid identification and characterization of angiogenesis and angiogenic modulators

Angiogenesis is a general term describing formation of new tube-like microvessel sprouts that are the size of capillary blood vessels. Angiogenesis is fundamental in key stages of embryonic development, organ formation, and wound repair and is also involved in the development and progression of a variety of pathological conditions, including...

Drug-eluting stents studies in mice: Do we need atherosclerosis to study restenosis?

In 2001, the first human study with drug-eluting stents (DES) was published showing a nearly complete abolition of restenosis by using a sirolimus-eluting stent. This success was very encouraging to test new compounds in combination with the DES platform. Nevertheless, several other anti-restenotic compounds have been used in human clinical...

The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro

PLD-118 is a novel, oral antifungal drug, under development for the treatment of Candida infections. Possible metabolism of PLD-118 by rat, dog and human S9 liver homogenates and inhibition of human cytochrome P450 (CYP) enzymes were investigated. PLD-118 (10 and 100 μm) incubated for 0-60 min with S9 fractions and NADPH was determined by HPLC,...

Rescuing drug discovery: In vivo systems pathology and systems pharmacology

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...

Synthesis and biological evaluation of disubstituted N6- cyclopentyladenine analogues: The search for a neutral antagonist with high affinity for the adenosine A1 receptor

Novel 3,8- and 8,9-disubstituted N6-cyclopentyladenine derivatives were synthesised in moderate overall yield from 6-chloropurine. The derivatives were made in an attempt to find a new neutral antagonist with high affinity for adenosine A1 receptors. N6-Cyclopentyl-9- methyladenine (N-0840) was used as a lead compound. Binding affinities of the...

Prophylactic and therapeutic effects of a humanized monoclonal antibody against the IL-2 receptor (DACLIZUMAB) on collagen-induced arthritis (CIA) in rhesus monkeys

CIA in the rhesus monkey is an autoimmune-based polyarthritis with inflammation and erosion of synovial joints that shares various features with human rheumatoid arthritis (RA). The close phylogenetic relationship between man and rhesus monkey makes the model very suitable for preclinical safety and efficacy testing of new therapeutics with...

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

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...

The role of the low-density lipoprotein receptor-related protein (LRP) in the plasma clearance and liver uptake of recombinant single-chain urokinase-type plasminogen activator in rats

Urokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, recombinant single-chain u-PA (rscu-PA) expressed in E. coli is recognized by the Low-Density Lipoprotein Receptor-related Protein (LRP) on rat parenchymal liver cells. In this study we investigated the role of...

The chicken enucleated eye test (CEET): A practical (pre)screen for the assessment of eye irritation/corrosion potential of test materials

The enucleated eye test with chicken eyes (CEET) obtained from an abattoir proved to be a valuable and practical alternative for the 'traditional' enucleated eye test with eyes of laboratory rabbits. Since 1992, the CEET has been incorporated in standard contract toxicity testing at the Toxicology Division of the TNO Nutrition and Food Research...

Animal behavioral methods in neurotoxicity assessment: SGOMSEC joint report

Chemicals/CAS: Neurotoxins

Relevance of parameters related to fertility and reproduction in toxicity testing

Toxicity data of 37 compounds tested in both a subchronic study and one or more studies focused on reproduction were evaluated to obtain information on the significance of fertility and reproduction parameters in setting no-effect levels (NEL). It appeared that a) the test system aimed at reproduction and development was more sensitive than the...

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

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,...

Mutagenicity screening: General principles and minimal criteria. Report of a committee of the European Environmental Mutagen Society

A statement of general principles and minimal criteria for the screening of chemicals for potential mutagenicity in man that may be used as guidelines for regulatory agencies and industrial organisations. To make clear the potentialities and current limitations of short-term mutagenicity testing for the prediction of genetic and carcinogenic...