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W Brouwer

Publications and source records attributed to W Brouwer.

12 recordsLinked to original sources
PubMed2000

Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes.

PURPOSE: The lipophilic cation [Au(I)(dppe)2]+ [where dppe is 1,2-bis(diphenylphosphino)ethane] has previously demonstrated potent in vitro antitumour activity. We wished to determine the physicochemical basis for the cellular uptake of this drug, as well as of analogues including the 1:2 adducts of Au(I) with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype; n = 2, 3 and 4), and to compare in vitro and in vivo antitumour activity. METHODS AND RESULTS: Logarithmic IC50 values for the CH-1 cell line bore a parabolic dependence on drug lipophilicity, as measured either by high-performance liquid chromatography or by n-octanol-water partition. Cellular uptake of drug, as measured by inductively coupled plasma mass spectrometry, varied by over three orders of magnitude over the series. Logarithmic uptake had a parabolic dependence on drug lipophilicity but a linear relationship to logarithmic IC50 values. Free drug concentrations were determined under the culture conditions and logarithmic free drug IC50 values and uptake rates were linearly related to lipophilicity. Uptake of drug in vivo in tissue from murine colon 38 tumours was approximately proportional to the dose administered. Host toxicity varied according to lipophilicity with the most selective compound having an intermediate value. This compound was also the most active of those tested in vivo, giving a growth delay of 9 days following daily intraperitoneal dosing (10 days) at 4 micromol kg(-1) day(-1). It was also significantly more active than another lipophilic cation, MKT-077. CONCLUSIONS: Alteration of lipophilicity of aromatic cationic antitumour drugs greatly affects cellular uptake and binding to plasma proteins. Changes in lipophilicity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.

Animals↗
PubMed2000

A fair approach to discounting future effects: taking a societal perspective.

It is usually recommended that future costs and health effects are discounted at the same rate, usually 5%. In this paper it is argued that, from a societal perspective, this approach may be inappropriate for health effects. Instead of basing the discount rate for health effects on that for costs, it should be based on the real change in the (societal) valuation of health effects over time. Such valuation may change because of increasing life-expectancy and diminishing marginal utility of additional health effects over time.

Cost-Benefit Analysis↗
PubMed1999

The effectiveness of different rat IgG subclasses as IgE-blocking antibodies in the rat basophil leukaemia cell model.

The degranulation of mast cells in an allergic response is initiated by the aggregation of high-affinity IgE receptors (Fc epsilon RI) by IgE and antigen. Recently it has been shown that such degranulation can be inhibited by cross-linking Fc epsilon RI and low-affinity IgG receptors (Fc gamma RII) which are also expressed by mast cells. The ability of various monoclonal antibodies to block the degranulation of rat basophil leukaemia (RBL) cells sensitized with IgE antidinitrophenyl (DNP) antibodies has been investigated. Sensitized cells were challenged with immune complexes formed using varying concentrations of antigen, and of both high- and low-valency antigen. It is reported here that rat IgG1 antibodies, which are associated in the rat with a Th1-type response, act as highly effective blocking antibodies over a wide concentration range. Rat IgG2a antibodies, which are associated with a Th2-type response, were able only to inhibit degranulation when immune complexes were formed with very low concentrations of high-valency antigen (DNP32-HSA). Under these conditions, some inhibitory activity was seen with high-affinity murine IgA anti-DNP but not with low-affinity rat IgG2b anti-DNP antibody-containing immune complexes. In addition to this inhibitory activity, IgG2a antibodies were shown to be capable of inducing degranulation of cells via unoccupied Fc epsilon RI. These results demonstrate that blocking activity may arise via both inhibitory receptors and by masking of antigen.

Animals↗
PubMed1997

Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin.

The diaminocyclohexane platinum (Pt(DACH)) derivatives ormaplatin and oxaliplatin have caused severe and dose-limiting peripheral sensory neurotoxicity in a clinical trial. We hypothesized that this toxicity could vary in relation to the biotransformation and stereochemistry of these Pt(DACH) derivatives. We prepared pure R,R and S,S enantiomers of ormaplatin (Pt(DACH)Cl4), oxaliplatin (Pt(DACH)oxalato) and their metabolites (Pt(DACH)Cl2 and Pt(DACH)methionine) and assessed their peripheral sensory neurotoxicity and tissue distribution in the rat and in vitro anti-tumour activity in human ovarian carcinoma cell lines. The R,R enantiomers of Pt(DACH)Cl4, Pt(DACH)oxalato and Pt(DACH)Cl2, induced peripheral sensory neurotoxicity at significantly lower cumulative doses (18 +/- 5.7 vs 32 +/- 2.3 micromol kg(-1); P < 0.01) and at earlier times (4 +/- 1 vs 6.7 +/- 0.6 weeks; P = 0.016) during repeat-dose treatment than the S,S enantiomers. Pt(DACH)methionine enantiomers showed no biological activity. There was no difference between Pt(DACH) enantiomers in the platinum concentration in sciatic nerve, dorsal root ganglia, spinal cord, brain or blood at the end of each experiment. Three human ovarian carcinoma cell lines (41 M, 41 McisR and SKOV-3) showed no (or inconsistent) chiral discrimination in their sensitivity to Pt(DACH) enantiomers, whereas two cell lines (CH-1 and CH-1cisR) showed modest enantiomeric selectivity favouring the R,R isomer (more active). In conclusion, Pt(DACH) derivatives exhibit enantiomeric-selective peripheral sensory neurotoxicity during repeated dosing in rats favouring S,S isomers (less neurotoxic). They exhibited less chiral discrimination in their accumulation within peripheral nerves and in vitro anti-tumour activity.

Animals↗
PubMed1997

Time headway in car following and operational performance during unexpected braking.

The relation between car-following behaviour and braking performance was studied in a driving simulator. The theoretical perspective was that individual differences in tactical car-driving behaviour may be related to skills on the operational level of the driving task via a process of adaptation. In a sample of 16 young and middle-aged experienced drivers independent assessments were made of preferred time headway during car following and of braking skill. Starting from modern theories of visual-motor learning, braking performance was analyzed in terms of a reaction time component, an open-loop visual-motor component, and a closed-loop visual-motor component involving the precise adjustment of braking (timing and force) to the situation. The efficiency of the visual-motor component of braking was a strong and significant predictor of choice of time headway to the lead vehicle in such a way that less efficient braking indicated a preference for a longer time headway. This result supports the theory of adaptation on the individual level.

Adult↗
PubMed1991

Optical quantitation and radiographic diagnosis of incipient approximal caries lesions.

The objectives of this study were to test the applicability of photocell measurements in approximal caries diagnosis and to evaluate the use of radiographs as validating criterion. Forty extracted premolars were selected, and the progression of the approximal lesions was graded clinically and radiographically by three examiners. Each tooth was transilluminated from the occlusal surface, and the throughput of light at the approximal surface was measured by a photocell. Together with clinical examination, the results of microradiographic analysis served as validating criterion in this study. The results indicate that photocell measurements can be useful in the diagnosis of incipient approximal caries lesions. Radiographs have a restricted value as validating criterion in diagnostic studies pertaining to incipient caries.

Bicuspid↗
PubMed1988

Nuclear magnetic resonance relaxation in experimental brain edema: effects of water concentration, protein concentration, and temperature.

Proton relaxation times T1 and T2 of macromolecular solutions, bovine brain tissues, and experimental cat brain edema tissues were studied as a function of water concentration, protein concentration, and temperature. A linear relation was found between the inverse of the weight fraction of tissue water and the spin-lattice relaxation rate, R1, based on a fast proton exchange model for relaxation. This correlation was also found for the spin-spin relaxation rate, R2, of gray matter samples and macromolecular solutions at low concentrations. Concentrated solutions of protein-water samples showed an enhanced relaxation due to viscosity effects. The T2 of white matter was considerably lengthened with elevated water concentration, but showed no straightforward relation with the total tissue water content. The relaxation times of all samples increased with temperature, supporting the assumption of fast proton exchange in the model for relaxation. This was not found for white matter, in which T2 decreased with increasing temperature, which indicated that intermediate or even slow exchange was present. The relation found between relaxation times and tissue water content can be used to predict the amount of and/or increase in tissue water due to water-elevating processes such as edema.

Animals↗
PubMedDate not supplied

Divided attention years after severe closed head injury: the effect of dependencies between the subtasks.

Lesions of white matter which connects distant brain areas are characteristic for closed head injury (CHI). It was predicted that this impairs divided attention only if dependent subtasks are used which require communication between corresponding brain processes. Fourteen chronic severe CHI patients (mean age 42 years) and 14 healthy controls, matched on age, gender, and education, participated in an experiment on divided attention. A typical left hemisphere task and a typical right hemisphere task must be simultaneously performed in a condition where they are completely independent and in conditions with dependencies between the tasks. Only in the dependent conditions the CHI group showed poor divided attention performance.

Adult↗