The protein kinase C inhibitor CGP41251 suppresses cytokine release and extracellular signal-regulated kinase 2 expression in cancer patients.

Components of cell signaling pathways provide important targets for anticancer drugs. Protein kinase C (PKC) is a serine/threonine-specific kinase that regulates cell growth and differentiation. It is also implicated in tumor promotion. The staurosporine analogue CGP41251 is a PKC inhibitor, and it is currently in a Phase I clinical trial for treatment of advanced cancer. However, it is difficult to define its biological activity. We have used two approaches to measure the in vivo biological response to CGP41251: (a) sequential whole blood samples were taken from 27 patients before and during treatment and incubated with mitogen (PHA), and cytokine [tumor necrosis factor (TNF)-alpha and interleukin (IL)-6] release was measured ex vivo; and (b) peripheral blood lymphocytes were isolated from seven of these patients, and the levels of extracellular signal-regulated kinase 2 were measured by Western blotting. Response to PHA was significantly lowered during treatment (P < 0.001 for TNF-alpha production; P < 0.03 for IL-6). This was most evident at 7 and 28 days after the start of treatment in patients receiving higher doses (150-300 mg/day; P = 0.002 and P = 0.02, respectively, for TNF-alpha and P = 0.001 and P = 0.003, respectively, for IL-6 release). Whole blood cytokine production returned to pretreatment levels after drug administration ceased. The levels of extracellular signal-regulated kinase 2 were reduced by 50-97% during treatment in all seven patients tested. These results show for the first time that a PKC inhibitor can block in vivo signaling pathways in cancer patients. The assays we describe complement toxicity studies in selecting relevant doses for Phase II trial of novel agents, particularly when biological activity occurs at doses below those that cause obvious side effects.

Selecting valid in vitro biocompatibility tests that predict the in vivo healing response of synthetic vascular prostheses.

We have investigated the usefulness of six in vitro biocompatibility tests in predicting the healing performance of polyester vascular prostheses as observed in previous canine in vivo trials. Vascular grafts were evaluated by using (i) a direct contact (DC) assay, (ii) an extract dilution (ED) assay on murine fibroblast cells, (iii) a DC assay on endothelial cells, (iv) a complement activation study, (v) a leucocyte activation study of CD18 integrin subunit expression on human polymorphonuclear cells (PMNs) and (vi) interleukin-2 receptor expression on lymphocytes. Uncleaned polyester grafts had previously been associated with poor healing and gelatin-impregnated polyester grafts with delayed but satisfactory healing, whereas commercially cleaned polyester grafts had demonstrated excellent healing. Lightweight and heavyweight knitted and woven polyester grafts supplied specifically for this project were studied, each with a different surface condition, i.e. commercially available (CP), uncleaned (UP) and impregnated with gelatin (GP). The UP grafts induced fibroblast cytotoxicity according to the ED assay, poor migration and viability of endothelial cells, and an elevated expression of CD18 and interleukin-2 receptor on PMNs and lymphocytes, respectively. In contrast, the CP grafts promoted good endothelial cell growth, no evidence of cytotoxicity and a weaker cell activation, and the GP grafts were found to be non-cytotoxic, to exhibit a good cellular response and to moderate cell activation. The complement activation assay and the DC assay on fibroblasts were found to be less useful and less discriminating. From this, it is concluded that the two cell activation measurements, the DC assay on endothelial cells and ED assay on fibroblasts, are useful in predicting the in vivo healing response of arterial polyester substitutes.

Gas chromatography-mass spectrometry determination of the migration of phthalate plasticisers from polyvinyl chloride toys and childcare articles.

Two laboratory-based linear horizontal agitation methods for determining a range of phthalate esters from soft polyvinyl chloride (PVC) toys are presented in compliance with EU legislation. Both of these methods were validated through interlaboratory trials using a PVC reference disc and four soft PVC toy/childcare articles intended or likely to be mouthed. Two of these commercial samples contained diisononyl phthalate (DINP), one diisodecyl phthalate (DIDP) and one bis(2-ethylhexyl) phthalate (DEHP). Acceptable repeatability (r, within-laboratory) and reproducibility (R, between-laboratory) data were demonstrated for both the analytical detection technique (GC-MS) (r = 9.8% and R = 8.1%) and agitation/extraction procedure (r=21.9% and R = 35.3% at 37 degrees C; r = 22.7% and R = 31.1% at 65 degrees C) for DINP. This was achieved through the participation of six laboratories. The remaining three phthalates from the EU Scientific Committee for Toxicity, Ecotoxicity and the Environment (CSTEE) list--dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and di-n-octyl phthalate (DnOP)--were not tested due to the unavailability of suitable materials.

Effect of pH on the nuclear magnetic resonance relaxivity of encapsulated solid paramagnetic substances.

Encapsulation, by acid-stable materials, of solid paramagnetic metal complexes based on sulphonated polystyrene ion-exchange resin, prevents the significant demetallation which otherwise occurs when the complexes are subjected to an acidic environment equivalent to that of the human stomach (pH 1-2). In turn, this protects the ability of those complexes to enhance the nuclear magnetic resonance (NMR) spin-lattice relaxation rate of water. Application of the results in the development of contrast agents for MR imaging of the gastrointestinal (GI) tract, in the evaluation of coatings used in drug formulations, and in the measurement of GI transit times of drugs is suggested.

Polymeric controlled release systems.

There are wide applications of great importance for the improved and efficient administration of many materials--particularly in the pharmaceutical area. The introduction of novel polymeric materials and related formulation technologies now provide a versatile means for the precisely controlled delivery of many physiologically active substances. A further advantage is a decrease in patient discomfort and compliance, and decreased side-effects.

The biocompatibility of glass-poly(alkenoate) (Glass-Ionomer) cements: a review.

The literature describing the biocompatibility of glass-poly(alkenoate) ('Glass-Ionomer') cements has been reviewed. This literature shows that these materials have generally good biocompatibility for both dental and orthopaedic use, this latter observation being very recent. There have, though, been a few reports showing that in certain circumstances these materials may cause pulpal irritation and the reasons for these particular findings are considered. Following discussion of the biocompatibility of Glass-Ionomer cements, consideration is given to the likely underlying causes of this feature. Three factors are identified as contributing to the biocompatibility of these cements. They are: (i) minimal exotherm on setting; (ii) rapid neutralization following mixing; and (iii) slow release of ions which are generally biologically beneficial or, at least, benign. This last point is considered in some detail. Previous studies of leaching of ions from Glass-Ionomer cements have shown that only inorganic species are released. The biological effects of each of these inorganic ions are described and their influence on biocompatibility discussed.

Isolated scaphotrapeziotrapezoid osteoarthritis: prevalence, symptomatology and associated scapholunate ligament disruption in a population presenting to an accident and emergency department with acute wrist injuries.

AIM: To determine the prevalence of isolated scaphotrapeziotrapezoid osteoarthritis in a population presenting to an Accident and Emergency Department of Leicester Royal Infirmary with acute wrist injuries. Also to identify the presence of scapholunate ligament disruption in this patient group and quantify symptoms and loss of function in terms of the modified system of Green and O'Brien, a recognized clinical scoring system. MATERIALS AND METHODS: A total of 1711 radiographs of patients attending the Accident and Emergency Department were prospectively reviewed over a 5-month period. Those patients with isolated scaphotrapeziotrapezoid osteoarthritis were invited for clinical review. RESULTS: Sixteen patients were identified with isolated scaphotrapeziotrapezoid osteoarthritis. Two had a poor Green and O'Brien score and evidence of scapholunate ligament disruption (P < 0.05). CONCLUSION: Isolated scaphotrapeziotrapezoid osteoarthritis has a prevalence of 1% in a population presenting to an Accident and Emergency Department with acute wrist injuries over the age of 30 years. Isolated scaphotrapeziotrapezoid osteoarthritis may be asymptomatic even though the changes in the joint are severe. Scapholunate ligament disruption is associated with a poor Green and O'Brien score, but is not present in the majority of cases. Higginson, A. P.et al. (2001). Clinical Radiology56, 372-374.