Evaluating the accuracy of using population pharmacokinetic data to predict plasma concentrations of alfentanil

A major reason for quantitating the relationship of drug dose to plasma concentration is to design optimal drug administration schemes (i.e., those that can achieve desired target concentrations of a drug). Recently, the authors completed a population pharmacokinetic analysis of the new opioid alfentanil using the computer program NONMEM. This analysis quantified the effects of age, weight, and sex on disposition of alfentanil in 45 patients, and determined the average pharmacokinetic profile of the drug for the group. Using these population pharmacokinetic parameters, one can predict (estimate) the plasma concentration time course of alfentanil for any given dosage scheme. The present study evaluated the accuracy with which one could use these population data to predict plasma concentrations of alfentanil in a different group of surgical patients given iv boluses and a variable-rate infusion of alfentanil for induction and maintenance of anesthesia for abdominal and superficial surgery. A total of 597 plasma concentrations of alfentanil were measured for 19 patients. For each measured concentration, we used the population pharmacokinetic parameters obtained previously with NONMEM to calculate a predicted concentration. Accuracy and precision of the prediction were assessed by the mean bias of the prediction and by the mean absolute prediction error, respectively. The mean bias (+/- SE) (systematic over- or underprediction) was -7.9 +/- 5.2%. The mean absolute error (+/- SE), a measure of the precision, was 22.3 +/- 2.9%. Therefore, the authors' previously described population pharmacokinetic parameters for alfentanil appear to be "robust," and can be used to design computerized schemes for administration of alfentanil for general surgery.     

Role of adhesins and toxins in invasion of human tracheal epithelial cells by Bordetella pertussis

Bordetella pertussis, the agent of whooping cough, can invade and survive in several types of eukaryotic cell, including CHO, HeLa 229, and HEp-2 cells and macrophages. In this study, we analyzed bacterial invasiveness in nonrespiratory human HeLa epithelial cells and human HTE and HAE0 tracheal epithelial cells. Invasion assays and transmission electron microscopy analysis showed that B. pertussis strains invaded and survived, without multiplying, in HTE or HAE0 cells. This phenomenon was bvg regulated, but invasive properties differed between B. pertussis strains and isolates and the B. pertussis reference strain. Studies with B. pertussis mutant strains demonstrated that filamentous hemagglutinin, the major adhesin, was involved in the invasion of human tracheal epithelial cells by bacteria but not in that of HeLa cells. Fimbriae and pertussis toxin were not found to be involved. However, we found that the production of adenylate cyclase-hemolysin prevents the invasion of HeLa and HTE cells by B. pertussis because an adenylate cyclase-hemolysin-deficient mutant was found to be more invasive than the parental strain. The effect of adenylate cyclase-hemolysin was mediated by an increase in the cyclic AMP concentration in the cells. Pertactin (PRN), an adhesin, significantly inhibited the invasion of HTE cells by bacteria, probably via its interaction with adenylate cyclase-hemolysin. Isolates producing different PRNs were taken up similarly, indicating that the differences in the sequences of the PRNs produced by these isolates do not affect invasion. We concluded that filamentous hemagglutinin production favored invasion of human tracheal cells but that adenylate cyclase-hemolysin and PRN production significantly inhibited this process.     

Current understanding of cellular and molecular events in intervertebral disc degeneration: implications for therapy

Until recently, material removed from the intervertebral disc (IVD) at surgery consisted either of 'loose bodies' from the centre of the IVD or discal tissue displaced (prolapsed) into the intervertebral root or spinal canals. This material is best regarded as a by-product of disc degeneration and therefore not representative of the disease process itself. Recent advances in surgical techniques, particularly anterior fusion, in which large segments of the anterior part of the IVD are excised with the anatomical relationships between different components intact, have generated material that can be investigated with modern molecular and cell biological techniques. This is an important area of study because degeneration of the lumbar IVDs is associated, perhaps causally, with low back pain, one of the most common and debilitating conditions in the West. 'Degeneration' carries implications of inevitable progression of wear-and-tear associated conditions. Modern research on human IVD tissue has shown that this is far from the case and that disruption of the micro-anatomy described as degeneration is an active process, regulated by locally produced molecules. The exciting consequence of this observation is the possibility of being able to inhibit or even reverse the processes of degeneration using targeted therapy.     

3,4-Dihydroxyphenylacetic acid (DOPAC) as an index of noradrenaline turnover: Effects of hydergine® and vincamine

Summary Among the drugs commonly used in the treatment of memory disorders of the elderly, vincamine and hydergine^® have been shown to moderately increase the firing rate of noradrenergic locus coeruleus (LC) neurons. Since changes in electrical activity of noradrenergic neurons are generally reflected in corresponding alterations of the turnover of this transmitter, the effects of these drugs on the accumulation of 3,4-dihyroxyphenylacetic acid (DOPAC) and dopamine (DA) in the presence and absence of the dopamine--hydroxylase inhibitor, FLA 63, were studied in the LC as well as in two of its projection areas, the hippocampus and the cerebellum. Characterization of this procedure with the ₂-adrenoceptor antagonist, idazoxan, the corresponding agonist, clonidine, the ₁-adrenoceptor antagonist prazosine, and haloperidol, suggested that- DOPAC changes are more suitable than those of DA or DOPAC/DA ratios in reflecting changes in noradrenaline (NA) turnover,- inhibiting DBH is advantageous if NA turnover is to be measured in projection areas, but not in LC, and- haloperidol and prazosine, in principle, did not affect NA turnover.Vincamine and hydergine^® at 10 mg/kg doses, at which they were reported to increase LC firing by 50%, did not induce a change in NA turnover in any of the areas. This, together with the data obtained with haloperidol, suggests that a minimal increase in the firing rate of LC cells (+140%) is required before it could influence the turnover of NA, as measured by DOPAC changes.Thus, the stimulating effect of nootropics on the central noradrenergic system may be more sensitively detected by electrophysiological techniques than by biochemical ones.     

Incidents et accidents lors de l’utilisation du fauteuil roulant électrique

The electric wheelchair (EW) is a medical device of which the marketing and safe usage are regulated; incidents concerning manufacturing faults are rare, evidenced by few materiovigilance reports with the ANSM (French National Agency for the Safety of Medicines and Health Products). Failures are primarily related to poor use or noncompliance with maintenance. Accidents would increase due to the increasing numbers of electric wheelchairs: falls constitute the main risk. Some preventive measures (particularly correct assessment of driving ability, etc.) are being increasingly implemented in order to avoid them.     

Oral health–related food selectivity among French independently living elders

Impaired oral conditions are described as influencing food intake behaviour and contributing to poor nutritional status in elderly persons. In order to evaluate the influence of age and oral factors on food choice among independently living elderly, we investigated food selectivity and oral health status in elders (aged over 65 years) and in younger people (aged between 35 and 64 years). Food selective behaviour was appraised by using a food selectivity questionnaire based on traditional French dishes. A stepwise binary logistic regression analysis was done to sequentially identify age and oral conditions associated with oral discomfort–related food avoidance. Occlusal status and oral health–related quality of life contributed to food choice. Risk of oral discomfort–related food avoidance was significantly increased in people with fewer than seven occlusal functional units (OFUs) and with Geriatric Oral Health Assessment Index summary scores (GOHAI-ADD) indicating poor and average oral health–related quality of life (P < .05). Age was never a significant factor of food selective behaviour. The present data support the impact of occlusal status and oral health–related quality of life on food behaviour. Specific attention should be given in maintaining or restoring good oral conditions throughout the lifespan, especially occluding teeth.     

Endocrine tumors of the duodenum. A study of 55 cases relative to clinicopathological features and hormone content

BACKGROUND/AIMS: Study of prognosis of duodenal endocrine tumors. METHODOLOGY: Retrospective study concerned 55 duodenal endocrine tumors discovered in biopsy or surgical specimens. Follow-up records available for 49 patients indicated that inconspicuous associated clinical manifestations were often found subsequently. Seven patients were classified as Zollinger-Ellison syndrome and seven as multiple endocrine neoplasia (6 MEN I and 1 MEN II). RESULTS: Tumors were small (mean 1.28cm) and located preferentially in the first and second part of the duodenum. Fifty-four were well-differentiated and one poorly differentiated. Immunochemistry revealed 30 G-cell tumors (54.6%), 15 D-cell (27.3%), two plurihormonal (EC cell and G cell), and one GRH-cell, whereas seven could not be classified. Fifteen patients died (five in relation to their disease). Twenty-one had metastases (liver, nodes, lung), eight of whom are still alive. CONCLUSIONS: Eighty-eight percent of duodenal endocrine tumors were gastrinomas, small plurifocal tumors and somatostatinomas preferentially located in the ampullar region and diagnosed because of hematemesis or icterus. Size is an important prognostic factor in determining whether surgery is required. The prognosis is better for D- and G-cell tumors than pancreatic endocrine tumors. Duodenal endocrine tumors in multiple endocrine neoplasia have a good prognosis, but can be associated with pancreatic plurihormonal tumors and metastases.