Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

The non-linear plasma pharmacokinetics of paclitaxel in patients has been well established, however, the exact underlying mechanism remains to be elucidated. We have previously shown that the non-linear plasma pharmacokinetics of paclitaxel in mice results from Cremophor EL. To investigate whether Cremophor EL also plays a role in the non-linear pharmacokinetics of paclitaxel in patients, we have established its pharmacokinetics in patients receiving paclitaxel by 3-, 24- or 96-h intravenous infusion. The pharmacokinetics of Cremophor EL itself was non-linear as the clearance (Cl) in the 3-h schedules was significantly lower than when using the longer 24- or 96-h infusions (Cl175–3 h = 42.8 ± 24.9 ml h−1 m−2; Cl175–24 h = 79.7 ± 24.3; P = 0.035 and Cl135–3 h = 44.1 ± 21.8 ml h−1 m−1; Cl140–96 h = 211.8 ± 32.0; P < 0.001). Consequently, the maximum plasma levels were much higher (0.62%) in the 3-h infusions than when using longer infusion durations. By using an in vitro equilibrium assay and determination in plasma ultrafiltrate we have established that the fraction of unbound paclitaxel in plasma is inversely related with the Cremophor EL level. Despite its relatively low molecular weight, no Cremophor EL was found in the ultrafiltrate fraction. Our results strongly suggest that entrapment of paclitaxel in plasma by Cremophor EL, probably by inclusion in micelles, is the cause of the apparent nonlinear plasma pharmacokinetics of paclitaxel. This mechanism of a (pseudo-)non-linearity contrasts previous postulations about saturable distribution and elimination kinetics and means that we must re-evaluate previous assumptions on pharmacokinetics–pharmacodynamics relationships. © 1999 Cancer Research Campaig

Is there an ideal way to initiate antiplatelet therapy with aspirin? A crossover study on healthy volunteers evaluating different dosing schemes with whole blood aggregometry

<p>Abstract</p> <p>Background</p> <p>Guidelines recommend an early initiation of aspirin treatment in patients with acute cerebral ischemia. Comparative studies on the best starting dose for initiating aspirin therapy to achieve a rapid antiplatelet effect do not exist. This study evaluated the platelet inhibitory effect in healthy volunteers by using three different aspirin loading doses to gain a model for initiating antiplatelet treatment in acute strokes patients.</p> <p>Methods</p> <p>Using whole blood aggregometry, this study with a prospective, uncontrolled, open, crossover design examined 12 healthy volunteers treated with three different aspirin loading doses: intravenous 500 mg aspirin, oral 500 mg aspirin, and a course of 200 mg aspirin on two subsequent days followed by a five-day course of 100 mg aspirin. Aspirin low response was defined as change of impedance exceeding 0 Ω after stimulation with arachidonic acid.</p> <p>Results</p> <p>Sufficient antiplatelet effectiveness was gained within 30 seconds when intravenous 500 mg aspirin was used. The mean time until antiplatelet effect was 74 minutes for 500 mg aspirin taken orally and 662 minutes (11.2 hours) for the dose scheme with 200 mg aspirin with a high inter- and intraindividual variability in those two regimes. Platelet aggregation returned to the baseline range during the wash-out phase within 4 days.</p> <p>Conclusion</p> <p>Our study reveals that the antiplatelet effect differs significantly between the three different aspirin starting dosages with a high inter- and intraindividual variability of antiplatelet response in our healthy volunteers. To ensure an early platelet inhibitory effect in acute stroke patients, it could be advantageous to initiate the therapy with an intravenous loading dose of 500 mg aspirin. However, clinical outcome studies must still define the best way to initiate antiplatelet treatment with aspirin.</p

Driving risk assessment under the effect of alcohol through an eye tracking system in virtual reality

The issue of driving under the effect of alcohol is a matter of several studies in the field of road safety because today alcohol is widely diffused especially among very young people (age ranging between 18 and 25). Each year data provided by authorities are worrying, more than a third of the accidents registered in European countries are caused by alcohol. Italy is aligned with this trend; the ISS – National Institute of Health estimates that alcohol-related road accidents are equal to 30–35% of the total road accidents. Medical researches confirm that alcohol generates negative effects on driving, impairs the ability of perception, attention, processing and evaluation and it has negative effects on cognitive and motor skills. Therefore, the present research is developed in the field of a wider project research with the purpose to investigate and estimate the impact of alcohol on road safety to support awareness campaigns “Drink or Drive”. As demonstrated by findings of the previous study, alcohol has a significant impact on driving performances in terms of geometric, kinematic and dynamic measures. Trajectory, stopping and overtaking maneuvers were studied and a significant delay in reflexes, especially in stopping and overtaking maneuvers, that exposes drivers to high risk level, was calculated. In this research, the focus is on the drivers’ eye-movements that are recorded in the virtual reality driving experiment. To understand how much alcohol impairs attention and concentration in relation to the driving performances, these data are processed and two eye blinking measures (i.e. % blinking and blink rate) are analyzed A sample of 20 drivers were requested to drive the virtual reality-driving simulator situated in the LASS3 Virtual Reality Laboratory of University Research Centre for Road Safety. The route runs in extra-urban and urban areas, in order to study drivers’ behavior in different cases and subjecting drivers to different stimuli (i.e. pedestrian crossing, overtaking maneuver, sudden braking, etc.). The results are a comparison between the results of two conditions drunken and sober. Results show that alcohol affects attention and concentration increasing the absolute value of blinking and its rate. During the stopping and the overtaking maneuvers where driving measures show higher risk levels in drunkenness condition respect the to the sober one, eye measures show a reduction in blinking and frequency (in both conditions) on behalf of a more attention to the road