The relevance of therapeutic drug monitoring in plasma and erythrocytes in anti-cancer drug treatment.

Therapeutic drug monitoring generally focuses on the plasma compartment only. Differentiation between the total plasma concentration and the free fraction (plasma water) has been described for a number of limited drugs. Besides the plasma compartment, blood has also a cellular fraction which has by far the largest theoretical surface and volume for drug transport. It is with anti-cancer drugs that major progress has been made in the study of partition between the largest cellular blood compartment, i.e., erythrocytes, and the plasma compartment. The aim of the present review is to detail the progress made in predicting what a drug does in the body, i.e., pharmacodynamics including toxicity and plasma and/or red blood cell concentration monitoring. Furthermore, techniques generally used in anti-cancer drug monitoring are highlighted. Data for complex Bayesian statistical approaches and population kinetics studies are beyond the scope of this review, since this is generally limited to the plasma compartment only.     

Mesenteric vein thrombosis associated with primary cytomegalovirus infection: a case report.

In the past few years several studies have supported an interplay between cytomegalovirus infections and a prothrombotic state. We describe a case of primary cytomegalovirus infection in an immunocompetent adult that was complicated with mesenteric vein thrombosis. Transient protein C deficiency, lupus anticoagulant and activated protein C resistance were found, in combination with a heterozygous prothrombin G20210A mutation. We discuss the possible mechanisms of cytomegalovirus-related venous thrombosis.     

Development of three parallel cytochrome P450 enzyme affinity detection systems coupled on-line to gradient high-performance liquid chromatography.

A high resolution screening (HRS) technology is described, in which gradient high-performance liquid chromatography (HPLC) is connected on-line to three parallel placed bioaffinity detection systems containing mammalian cytochromes P450 (P450s). The three so-called enzyme affinity detection (EAD) systems contained, respectively, liver microsomes from rats induced by beta-naphthoflavone (CYP1A activity), phenobarbital (CYP2B activity), and dexamethasone (CYP3A activity). Each P450-EAD system was optimized for enzyme, substrate, and organic modifier (isopropyl alcohol, methanol, and acetonitrile) in flow injection analysis mode. Characteristic P450 ligands were used to validate the P450-EAD systems. IC(50) values of the ligands were measured and found to be similar to those obtained with conventional microtiter plate reader assays. Detection limits (n = 3; signal-to-noise ratio = 3) of potent inhibitors ranged from 1 to 3 pmol for CYP1A activity, 4 to 17 pmol for CYP2B activity, and 4 to 15 pmol for CYP3A activity. The three optimized P450-EAD systems were subsequently coupled to gradient HPLC and used to screen compound mixtures for individual ligands. Finally, to increase analysis efficiency, a HRS system was constructed in which all three P450-EAD systems were coupled on-line and in parallel to gradient HPLC. The triple parallelized P450-EAD system was shown to enable rapid profiling of individual components in complex mixtures for inhibitory activity to three different P450s.     

VISUOMOTOR PERFORMANCE OF NORMAL AND CLUMSY CHILDREN. II: ARM-TRACKING WITH AND WITHOUT VISUAL FEEDBACK

Tracking performance was investigated in normal and clumsy children in two age-groups, six to seven and 10 to 11 years. Target signals moving unpredictably along a straight line had to be tracked, both with and without visual feedback. Performance was described in three ways: (1) performance in the low-frequency range (LF); (2) the delay between target signal and tracking movement (DL); and (3) a measure of tracking quality or over-all similarity in the shape of target signal and tracking movement (Q). Clumsy children in both age-groups had a lower tracking quality (Q) and longer delay (DL) than the normal children. Disturbances in the regulation of attention seemed to affect tracking performance, particularly of the six- to seven-year-old clumsy children. There was no significant difference between normal and clumsy children in the effect of visual feedback on tracking performance. This suggests that clumsiness is not linked to disturbance of integration of visual feedback information and motor processes.     

In vivo (31)P magnetic resonance spectroscopy and morphometric analysis of the perfused vascular architecture of human glioma xenografts in nude mice.

The relationship between the bioenergetic status of human glioma xenografts in nude mice and morphometric parameters of the perfused vascular architecture was studied using (31)P magnetic resonance spectroscopy (MRS), fluorescence microscopy and two-dimensional digital image analysis. Two tumour lines with a different vascular architecture were used for this study. Intervascular distances and non-perfused area fractions varied greatly between tumours of the same line and tumours of different lines. The inorganic phosphate-nucleoside triphosphate (P(i)/NTP) ratio increased rapidly as mean intervascular distances increased from 100 microm to 300 microm. Two morphometric parameters - the percentage of intervascular distances larger than 200 microm (ivd200) and the non-perfused area fraction at a distance larger than 100 microm from a nearest perfused vessel (area100), - were deduced from these experiments and related to the P(i)/NTP ratio of the whole tumour. It is assumed that an aerobic to anaerobic transition influences the bioenergetic status, i.e. the P(i)/NTP ratio increased linearly with the percentage of ivd200 and the area100.     

A postoperative analysis of the patient''s view of anaesthesia in a Netherlands'' teaching hospital

A postoperative questionnaire was used in 129 patients who had undergone a wide range of surgical procedures in order to investigate their personal experience of anaesthesia. The most frequent complaints were of feeling cold on waking up, sore throat, vomiting and muscle pains, all of which are capable of reduction by a change in anaesthetic technique. The total number of patients who had one or more complaints was 107 (82.9%). More than a third of the patients were afraid of the anaesthetic, as distinct from the operation. Most had received a pre-operative visit from the anaesthetist which was greatly appreciated. A few patients believed they could have been better informed of possible sequelae. More than 30% were not visited by the surgeon before the operation. A routine postoperative interview, using a preformulated questionnaire, is a good way to assess and maintain a high quality of anaesthesia.     

Modulation of histamine release by rat peritoneal mast cells in a superfusion set-up.

A new method is presented for studying mediator release in isolated peritoneal cells of the rat. Using a superfusion technique, cells can be maintained in a continuously cleared medium. Cells were stimulated with antigen, compound 48/80 or A23187 to characterize this preparation. In addition, inhibitory effects of theophylline, isoprenaline and cromoglycate on compound 48/80-induced histamine release were studied. We conclude that superfusion is a valid alternative to study mediator release from isolated peritoneal cells.     

Corneal epithelial barrier function after oxybuprocaine provocation in diabetics

Corneal epithelial permeability for fluorescein was determined after provocation by a local anesthetic in 18 non-insulin-dependent diabetes mellitus (NIDDM) patients, 23 insulin-dependent diabetes mellitus (IDDM) patients, and 22 healthy controls to evaluate the corneal epithelial barrier function in diabetes. All volunteers had Oxybuprocaine instilled into one eye and saline into the other eye. The epithelial permeability values were determined by fluorophotometry, and the ratio between both eyes was calculated for each individual. The mean permeability values of the saline-instilled eyes in the diabetic patients did not differ significantly from those in the healthy controls (P greater than 0.2). The individual ratios between Oxybuprocaine- and saline-instilled eyes in the NIDDM and IDDM patients differed significantly from those in the healthy controls (mean ratios: 2.6, 1.9, and 1.0, respectively; P less than 0.002). The permeability ratios and the percentage glycosylated hemoglobin (HbAlc) were linearly correlated in the NIDDM patients but not in the IDDM patients (r = 0.73, P less than 0.001, and r = 0.09, P greater than 0.68, respectively). The results showed that the corneal epithelial barrier function in the diabetic patients was not impaired compared with that in the healthy controls. After provocation by a local anesthetic, the barrier function was impaired in the diabetic patients only.