Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery.

While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation and vascular remodelling upon vascular damage. The aim of this study was to examine the effects of aspirin and/or rivaroxaban on injury-induced murine arterial thrombus formation in vivo and in vitro, vessel-wall remodelling, and platelet-leukocyte aggregates. Temporary ligation of the carotid artery of C57BL/6 mice, fed a western type diet, led to endothelial denudation and sub-occlusive thrombus formation. At the site of ligation, the vessel wall stiffened and the intima-media thickened. Aspirin treatment antagonized vascular stiffening and rivaroxaban treatment led to a positive trend towards reduced stiffening. Local intima-media thickening was antagonized by both aspirin or rivaroxaban treatment. Platelet-leukocyte aggregates and the number of platelets per leukocyte were reduced in aspirin and/or rivaroxaban treatment groups. Furthermore, rivaroxaban restricted thrombus growth and height in vitro. In sum, this study shows vascular protective effects of aspirin and rivaroxaban, upon vascular injury of the mouse artery.

Method for measurement of arterial compliance by fusion of oscillometry and pulse wave velocity.

Up until now estimation of arterial compliance has been performed either by analysis of arterial pressure changes with respect to volume changes or by inference based on pulse wave velocity (PWV). In this study we demonstrate the possibility of an approach to assess arterial compliance by fusing the two information sources namely the pressure/volume relationship obtained from oscillography and PWV data. The goal is to assess arterial properties easily and robustly, enhancing current hemodynamic monitoring. The approach requires as input signals: an electrocardiogram (ECG), a photo- plethysmogram (PPG) and the arterial oscillation as measured during non-invasive blood pressure measurements based on oscillometry with a cuff. These signals are fused by an algorithm using Bayesian principles underpinned by a physiological model. In our simulations, we demonstrate the feasibility to infer arterial compliance by our proposed strategy. A very first measurement on a healthy volunteer supports our findings from the simulation.Clinical Relevance- Arterial compliance/stiffness is recognized as a key hemodynamic parameter, which is not easily accessible and not a standard parameter currently. The presented method and obtained results are encouraging for future research in this area.

Using a clinical decision support system to determine the quality of antimicrobial dosing in intensive care patients with renal insufficiency.

BACKGROUND: The benefits on clinical practice of a clinical decision support system (CDSS) are predominantly determined by the quality of the clinical rules used in this system. Therefore, it is essential to investigate the performance and potential benefits on quality of care of these rules. METHODS: A clinical rule assisting physicians in selecting the appropriate dosage according to renal function of frequently prescribed antimicrobials was developed. In 2004, 1788 patients admitted to the intensive care unit (ICU) for more than 12 h were included in this retrospective study. The actual number of dosage adjustments without the support of the CDSS was compared with the theoretical number of dosage adjustments determined by the clinical rule in patients with moderate (creatinine clearance (Cl(creat)) 10-50 ml/min) and severe (Cl(creat) <10 ml/min) renal dysfunction. If dosage adjustment was omitted, the duration of excessive anti-infective dosing and extra drug costs involved was determined. RESULTS: Dosage adjustment of antimicrobials was omitted in 163 patients (86%) with moderate renal failure and 13 patients (54%) with severe renal failure. Excessive exposure was most frequently detected in patients receiving fluconazole and ciprofloxacin (median duration of 6 days). In our ICU alone, more than 16,000 euro ($19 000) can be saved annually by adjusting the dosage according to renal function of frequently prescribed antimicrobials. CONCLUSIONS: Despite intensive monitoring of patients in the ICU, dosage adjustment of antimicrobials is often omitted. Implementing this clinical rule has the potential to contribute to a significant improvement in medication safety and is expected to generate substantial savings.

Diffusion of n-butyl-p-aminobenzoate (BAB), lidocaine and bupivacaine through the human dura-arachnoid mater in vitro.

INTRODUCTION: Epidural administration of a suspension of n-butyl-p-aminobenzoate (BAB) to humans resulted in a selective, ultra-long lasting sensory block without motor function impairment. The absence of motor block was attributed to 'spatial' confinement of active concentrations of dissolved BAB within the epidural space. This study was designed to investigate the diffusion of BAB through the human dura-arachnoid membrane in vitro relative to lidocaine and bupivacaine and to quantify the influence of the composition of the suspension formulation on this flux. MATERIALS AND METHODS: Human dura-arachnoid specimens were mounted between the donor and the receiver compartment of a diffusion cell. Five concentrations of BAB, lidocaine and bupivacaine in phosphate-buffered saline, pH 7.4, were added to the donor compartment and the increase of the concentration of the agent in time in the receiver compartment was measured by automated UV-spectrometry. Fluxes and permeabilities were calculated. The influence of pH, polysorbate 80 (PS 80) and polyethylene glycol 3350 (PEG 3350) on the flux of BAB in solution and in suspension formulations were analyzed. RESULTS: The flux of both lidocaine and bupivacaine at pH 4 was considerably smaller than at pH 7.4. Permeabilities decreased in the order bupivacaine>lidocaine&z.Gt;BAB and at the level T12>T1. PS 80 at concentrations exceeding 0.025 mg/ml and PEG 3350 decreased the flux of BAB from BAB-solutions. Used in the preparation of the suspension, PS 80 and PEG 3350 did significantly reduce the permeability. DISCUSSION: The results of this study are consistent with the hypothesis that the selective action of epidurally applied BAB suspension can be attributed to the spatial confinement of active BAB-concentrations within the epidural space. Additives used in the preparation of the aqueous suspension formulation may substantially influence the local pharmacokinetics and by that the pharmacodynamic effects.

A phase II trial of gemcitabine in combination with 5-fluorouracil (24-hour) and folinic acid in patients with chemonaive advanced pancreatic cancer.

BACKGROUND: Gemcitabine (Gemzar) and 5-fluorouracil (5-FU) plus folinic acid (FA) both have proven activity in the treatment of patients with advanced pancreatic cancer. The present study was initiated to investigate the efficacy of gemcitabine in combination with 5-FU-FA. PATIENTS AND METHODS: Thirty-eight patients, median age 60 years (range 34-70) with inoperable, stage IV, pancreatic cancer were enrolled into the study and treated on an outpatient basis. All except one patient received at least one cycle of treatment with gemcitabine (1000 mg/m2), followed by FA (200 mg/m2) and 5-FU (750 mg/m2) administered as a 24-hour continuous infusion on days 1, 8, 15 and 22 of a 42-day schedule. No patient had received prior chemotherapy or radiotherapy. All 38 patients were assessed for efficacy, toxicity and time to progressive disease. RESULTS: Two patients (5%), achieved a partial response and thirty-four patients (89%) achieved stable disease. There were two early deaths (< or = 4 weeks). The median time to progression was 7.1 months (range 0.4-18.1+; 95% confidence interval (95% CI): 5.3-7.9 months). Three patients had a progression-free interval of greater than 12 months and 12 of 38 patients (32%) survived longer than 12 months. The median overall survival was 9.3 months (range 0.5-26.5; 95% CI: 7.3-13.0 months). The incidence of grade 3 and 4 toxicities was low. CONCLUSIONS: The combination of gemcitabine and 5-FU-FA is active and well tolerated and seems to offer an improvement in progression-free interval over both gemcitabine monotherapy and 5-FU-FA therapy.