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OBJECTIVE Over the last few years, there has been concern regarding the cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors and high-dose regimens of nonsteroidal anti-inflammatory drugs (NSAIDs). On the other hand, those compounds which elicit an almost complete (> 95%) and continuous suppression of platelet COX-1 may represent an exception. Apart from aspirin, which irreversibly inactivates COX-1, high-dose naproxen causes sustained COX-1 inhibition throughout the dose interval in some individuals. The present study examines whether naproxen sodium after a single dose administration and at steady state using "over-the-counter (OTC) doses" produces sufficient COX-1 inhibition. COX-2 inhibition was assessed concomitantly. METHODS Ex vivo inhibition of COX enzymes and the pharmacokinetics of naproxen were assessed in four volunteers receiving 220 mg naproxen sodium b.i.d. for 7 days. Blood samples were obtained pre-dose, at specified time points after the first dose on Day 1, and 12 hours after the previous evening dose on Days 2, 3, 4, 5 and 8. Recovery was assessed up to 36 hours after the last dose. Coagulation-induced thromboxane B2 formation and lipopolysaccharide-induced prostaglandin E2 synthesis were measured ex vivo in human whole blood as indices of COX-1 and COX-2 activity. RESULTS Maximal inhibition after a single dose and at steady state were as follows: 94% and 93% (COX-1), and 79% and 85% (COX-2). A greater than 95% COX-1 inhibition was observed transiently in 2 of 4 volunteers at the time of maximal plasma concentration after a single-dose administration and in 1 of 4 volunteers throughout the 12-hour dose interval at steady state. For both isoenzymes, COX inhibition correlated with naproxen plasma levels (ex vivo IC50 values of 35.48 micromol/l (COX-1) and 64.62 micromol/l (COX-2)). CONCLUSIONS Administration of naproxen sodium at OTC doses was associated with a profound inhibition of both COX enzymes. Although low-dose naproxen may elicit a virtually complete COX-1 inhibition in some individuals, it does not mimic the reliable, sustained and complete COX-1 blockade produced by aspirin. In conclusion, prolonged treatment with 220 mg naproxen sodium b.i.d. is not expected to provide sufficient cardioprotection in all patients, but may influence platelet function in some.

Introduction In European and International Standards and Directives, external loads in terms of daily vibration exposure A(8) or vibration dose value VDV are used as predictors of adverse health effects. These values only partly reflect the internal load acting on the lumbar spine. Particularly for shock containing acceleration time histories, a method for the calculation of internal spinal forces on the basis of a Finite-Element-Model (FEM) was developed within the EU VIBRISKS project [1]. The model can be adapted to the anthropometry (ten categories) and the sitting posture (six categories) of the driver. The method has been proposed in a working draft of the Standardisation Committee ISO/TC 108/SC 4/WG 15 [2]. It has already been standardised in the German Standard DIN SPEC 45697 [3]. The risk assessment is based on the daily compressive dose Sed (MPa) and the risk factor R (non-dimensional). Both values are determined by the compressive internal forces, by the daily and lifetime exposure duration and by the age at the start of exposure. For a re-analysis of the Italian part of an epidemiological study performed within the VIBRISKS project, the internal forces, Sed and R were calculated for the 537 participants of the study. Methods Typical acceleration time histories for various machine types and working tasks were selected. Impacts due to sitting down or loosing the contact to the seat were eliminated. At the end, 19 checked time histories with a duration of 200 s were available. All signals were shock containing [4]. Beside the calculation of Sed and R factor, r.m.s., r.m.q. and standard deviation of the time histories of the internal forces were assessed in all three axes separately and as a vector sum. Therefore, a modification of the program published on the CD in DIN SPEC 45697 had to be used, because it was necessary to get the interim results of the calculations in terms of internal forces. In the horizontal axes, the daily doses were calculated without relation to the spinal endplate areas. The daily doses for the internal forces acting in anterior and posterior directions were separately computed. In total, 21 different variables were calculated. Results The values of the forces, Sed and R factor varied over the lumbar spine levels from T12/L1 to L5/S1. The shapes of the spine-level dependent curves were determined by the posture and the type of machine (example for posture group1 in Fig. 1). The category of body mass and Body Mass Index (BMI) and the posture - in association with the covariates listed in Table 1 - significantly influenced the maximum R factor (statistical test: ANCOVA). The interaction between the body mass/BMI-category and the posture was not significant (F=1.3, p=0.11). When several machines in identical sitting posture were used, the type of machine showed a significant effect as well (Table 1, last three lines). In these cases, the effect of the yearly exposure duration was not longer calculated due to a lack of variability of the covariate. Instead of that, the last column of Table 1 contains the interaction between the body mass/BMI-category and the type of machine which was significant for all three postures. The p-value was p

Mit Hilfe einer Re-Analyse der Daten von 537 Teilnehmern an einer epidemiologischen Studie im EU-Projekt VIBRISKS [1] sollte untersucht werden, inwieweit geschätzte Risiken, die auf mit Modellen vorhergesagten intra-spinalen Kräften beruhen [2], das Risiko für Beschwerden und Schmerzen in der Lendenwirbelsäule widerspiegeln. Sämtliche Vibrationsexpositionen waren nach unterschiedlichen Kriterien stoßhaltig [3]. Im vorliegenden Beitrag werden die Ergebnisse ausgewählter Berechnungen dargestellt. Die Verteilung des Risikos über die Lendenwirbelsäule wurde von der Sitzhaltung und von der Art des Fahrzeugs bestimmt. Die Körpermasse / BMI- Kategorie und die Körperhaltung hatten einen signifikanten Einfluss auf den maximalen Risikofaktor. Darüber hinaus war der Risikofaktor war umso höher, je länger die tägliche und die jährliche Expositionszeit und die Lebensexpositionszeit, und je höher das Lebensalter bei Beginn der Exposition waren. Für einige Haltungen und Fahrzeugtypen erreichten die dynamischen Anteile der intra-spinalen Kräfte in x-Richtung Werte, die mit denen in vertikaler Richtung (Kompressionskräfte) vergleichbar waren, obwohl der A(8)-Wert in x-Richtung nur einen Bruchteil desselben in z-Richtung betrug. Für die Entwicklung eines Schädigungsmodells für die Wirbelsäule auf Basis der horizontalen intra-spinalen Kräfte besteht auch international Forschungsbedarf. Die individuelle Abschätzung des Risikos mit Hilfe der DIN SPEC 45697 hat sich auch für größere Exponiertengruppen als praktikabel erwiesen.