Establishing the dose-dependent daily variations of a low molecular weight heparin (Fraxiparine) through a population approach analysis in the rat.

The effects of dose and dosing time on the anticoagulant activity of a low molecular weight heparin (Fraxiparine) were studied in rats. Three doses were administered at four evenly spaced dosing times. Rats were kept under a light-dark cycle of 24h, and all the main external factors were constant. The bleeding time, the anti-Xa activity of the drug, and the activated partial thromboplastin time (APTT) were measured. A population approach analysis to assess daily variations was used. With standard methods, interindividual variability may mask potential time-related effects, while the population approach analysis overcomes this difficulty. Bleeding time was at its peak at 04:00 and at its trough at 22:00, suggesting that platelet activity was time of day dependent. For the pharmacological activity of the drug, we compared several pharmacokinetic models derived from a monocompartmental model. The model that describes the anti-Xa pharmacological activity best is expressed through parameters that depend on animal weight and drug level. The model for APTT is of a sinusoidal type for which the clearance depends on the dosing time. The most inter esting result is that the amplitude of this daily variation is linearly dependent on drug level.

Modifications of bone and connective tissue after orthostatic bedrest.

Eight male volunteers were submitted to a 6-week anti-orthostatic bedrest trial followed by a 1-month reambulation period. We prospectively monitored whole-body composition by dual-energy X-ray absorptiometry, bone and connective tissue metabolism by biochemical markers and calcium regulating hormones by 1-84 parathyroid hormone and 1,25-dihydroxyvitamin D(3). Bone mineral density (BMD) did not vary significantly; however, a trend toward an increase in head BMD and a decrease in trunk, lumbar vertebrae and lower limb BMD was observed. A decrease in the lower limb lean content occurred by day 27 and was maximum by day 42 after the beginning of bedrest; it normalized by day 30 after bedrest. The serum levels of both osteocalcin and C-terminal crosslinked telopeptide of type I collagen increased as a consequence of bedrest. A slight increase in the serum levels of the N-terminal propeptide of type III collagen, a marker of connective tissue metabolism, was observed during the bedrest period. Except for the C-terminal extension propeptide of type I collagen, all markers decreased to baseline pre-immobilization levels during the 1-month recovery phase. Serum PTH and 1,25-dihydroxyvitamin D(3) levels were low during the bedrest period and rose during the reambulation phase. These results seem to reflect early changes in bone and connective tissue metabolism as a result of bedrest unloading, but their order of magnitude remains moderate, thus emphasizing the necessity to perform longer-duration trials.

A chronopharmacodynamic study on standard heparin, a low molecular weight heparin (nadroparin) and danaproid: establishing and comparing the daily variations of these drugs in rats.

The effects of dosing time on the anticoagulant activity of unfractionated heparin, low molecular weight heparin (nadroparin) and danaproid were investigated. The chronopharmacological comparisons of the drugs were done on the anti-Xa, anti-IIa activities and activated partial thromboplastin time assays. Several dosing times were considered and an analysis based on a population approach was adopted. Under unfractionated heparin, the pharmacological activities did not exhibit significant daily variations. In contrast, significant daily profiles were observed in all the biological assays performed with low molecular weight heparin. Anti-Xa and anti-IIa activities showed some fluctuations over a 24-hour period with a peak at noon. As for the variations of the activated partial thromboplastin time, two peaks were noted early in the morning and at the beginning of nightfall. As for danaproid, only a daytime maximum of anti-Xa activity could be found.

The relations between physical ability and bone mass in women aged over 65 years.

In this cross-sectional study of 55 women (mean age 73.54 +/- 5.87), the magnitude of the relation between different indices of physical ability and confounding factors to bone density were determined. Physical fitness was assessed by direct measurement of maximal oxygen consumption (VO2 max), isokinetic muscle strength, and quadriceps and psoas muscle surfaces and densities using computed tomography. Anthropometry, chronological and gynecological ages, and dietary calcium intake were also recorded. The bone mineral density (BMD) was evaluated at the axial level (lumbar spine and proximal femur) and at the peripheral level (radius and tibia, cancellous and cortical compartments). Parameters related to physical ability proved to be the best predictors of BMD in radial and tibial cancellous compartments, spine, femoral neck, and trochanter, accounting for 15-27.5% of the total variance. The VO2 max was a major determinant of the femoral mineral density and one of the predictors of radial and tibial cancellous compartments. Psoas parameters were strongly related to spine mineral density and also constituted a predictor of radius (cancellous) and tibia mineral densities. The arm muscle strength could predict, though weakly, the BMD of axial skeleton, whereas thigh muscle strength only predicted the BMD of inferior limbs. No correlation was observed between current dietary calcium intake and BMD. Age-postmenopause and fertile life remained predictive of BMD at mostly cancellous sites, whereas anthropometry exerted important effects on radial and tibial cortices. The study suggests distinct sets of relations between physical ability and the BMD variables. Subjects with greater and denser psoas muscles had greater spine BMD, and those with higher VO2 max had greater proximal femur BMD.