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Purpose: Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis., Experimental Design: In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days., Results: For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration-time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime., Conclusion: Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies.

Physical whole-body vibration (WBV) exercises become available at various levels of intensity. In a first series of measurements, we investigated 3-dimensional platform accelerations of three different WBV devices without and with three volunteers of different weight (62, 81 and 100 kg) in squat position (150 degrees knee flexion). The devices tested were two professional devices, the PowerPlate and the Galileo-Fitness, and one home-use device, the PowerMaxx. In a second series of measurements, the transmission of vertical platform accelerations of each device to the lower limbs was tested in eight healthy volunteers in squat position (100 degrees knee flexion). The first series showed that the platforms of two professional devices vibrated in an almost perfect vertical sine wave at frequencies between 25-50 and 5-40 Hz, respectively. The platform accelerations were slightly influenced by body weight. The PowerMaxx platform mainly vibrated in the horizontal plane at frequencies between 22 and 32 Hz, with minimal accelerations in the vertical direction. The weight of the volunteers reduced the platform accelerations in the horizontal plane but amplified those in the vertical direction about eight times. The vertical accelerations were highest in the Galileo (approximately 15 units of g) and the PowerPlate (approximately 8 units of g) and lowest in the PowerMaxx (approximately 2 units of g). The second series showed that the transmission of vertical accelerations at a common preset vibration frequency of 25 Hz were largest in the ankle and that transmission of acceleration reduced approximately 10 times at the knee and hip. We conclude that large variation in 3-dimensional accelerations exist in commercially available devices. The results suggest that these differences in mechanical behaviour induce variations in transmissibility of vertical vibrations to the (lower) body.

Objective: We tested the hypothesis that betamethasone is more potent than dexamethasone in inducing the essential mechanisms of parturition in sheep., Methods: Twenty-one sheep were instrumented under general anesthesia with maternal and fetal arterial and venous catheters and myometrial electromyogram electrodes at 117 days' gestation (dGA). At 125 dGA at 12:00 PM, after 2 days of baseline recording, either saline (n = 7, control group), betamethasone (n = 7), or dexamethasone (n = 7) was administered into the fetal jugular vein at a rate of 10 micrograms/hour. A total dose of 0.48 mg was given over the next 48 hours. The animals underwent autopsy 3 days after the end of the infusion period (130 dGA), or earlier if labor resulted from the glucocorticoid administration. Daily maternal and fetal arterial blood samples (4 mL) for hormone measurement were taken at 10:00 AM throughout the study period. Additional arterial blood samples were taken if the animal developed labor. Maternal plasma progesterone and fetal ACTH and cortisol concentrations were measured by radioimmunoassay, and corticosteroid-binding globulin (CBG) binding capacity was determined by saturation analysis. Myometrial activity was monitored continuously throughout the experimental protocol., Results: All seven betamethasone-treated animals developed labor after the glucocorticoid infusion regimen. In contrast, only two of seven dexamethasone-treated animals developed labor. Fetal treatment with betamethasone produced a greater and earlier fall in maternal plasma progesterone than fetal treatment with dexamethasone. Both betamethasone and dexamethasone treatments elevated fetal plasma CBG to similar binding capacities. Elevated fetal plasma ACTH and cortisol concentrations at the end of the infusion period in both betamethasone-and dexamethasone-treated animals were not related to the development of labor-type contractions., Conclusion: These data support the hypothesis that betamethasone is more potent than dexamethasone in inducing the essential mechanisms of parturition in sheep.