Inhibition of plasma-dependent monocyte chemokinesis and cytokine-triggered endothelial activation for neutrophil transmigration by administration of clopidogrel in man.

Mediators released by spontaneously activated platelets may contribute to alterations in endothelial and leukocyte dysfunctions. We investigated the roles of clopidogrel and aspirin in ex vivo endothelial activation for interactions with leukocytes. Eight healthy volunteers received clopidogrel or aspirin for 8 days. Blood samples were taken before, during, and after treatment. Levels of adhesion molecules and platelet-derived mediators in these samples were measured using commercially available test kits, and effects of plasma on endothelial cells and leukocytes were investigated in neutrophil transendothelial migration, monocyte-endothelial adhesion and leukocyte migration assays. Plasma samples from clopidogrel-treated persons induced diminished chemokinesis of monocytes. Tumour necrosis factor-induced priming of endothelial cells for enhanced neutrophil transmigration was also diminished by pretreatment of endothelial cells, but not of neutrophils, with plasma derived from subjects during clopidogrel treatment. Plasma from the aspirin group had no such effects. Administration of clopidogrel but not aspirin significantly decreased serum levels of soluble intercellular adhesion molecule-1, whereas no changes in levels of soluble vascular cell adhesion molecule-1, P-selectin, L-selectin, von Willebrand factor, platelet-derived growth factor, vascular-endothelial growth factor, and transforming growth factor-beta were observed. Inhibition of plasma-promoted endothelial activation by clopidogrel may indicate a novel role in the prevention of atherosclerosis.

Pharmacokinetics of ciprofloxacin in patients with acute renal failure undergoing continuous venovenous haemofiltration: influence of concomitant liver cirrhosis.

To determine an adequate dosage of ciprofloxacin in critically ill medical patients on continuous venovenous haemofiltration, we studied the pharmacokinetics of ciprofloxacin in eight critically ill medical patients with renal failure treated with continuous venovenous haemofiltration using polysulfone membranes. Three of those patients also presented with severe liver dysfunction. For comparison, three patients with approximately normal renal function and two patients with impaired renal function were included. During haemofiltration, plasma concentrations of ciprofloxacin were variable. In all critically ill patients ciprofloxacin elimination was significantly slowed; the mean half-life was similarly prolonged to about 14 h in patients on haemofiltration and those with approximately normal renal function. In critically ill patients with impaired renal function not on haemofiltration, the mean half-life was longest. Ciprofloxacin clearance by haemofiltration was a quarter of the total clearance. Although a unique dose recommendation can hardly be made because of the high variability of pharmacokinetics during haemofiltration, a daily dose of 800 mg (400 mg b.i.d.) in average can be regarded as appropriated for reaching a target plasma concentration of 2 to 3 micrograms/mL (mean concentration). Because the half-life of ciprofloxacin was further prolonged by the presence of liver cirrhosis, the dose should be reduced to 600 mg in patients on haemofiltration with concomitant severe liver dysfunction.

The anti-inflammatory actions of antithrombin--a review.

Leukocyte-endothelial cell interaction and microvascular perfusion failure are characteristic deteriorations of the microcirculation in endotoxaemia and are known to play a crucial role in the development of septic multiple organ dysfunction. Recent studies have indicated that antithrombin III treatment is capable of significantly ameliorating these microcirculatory disorders. Endothelial cells have important anticoagulant systems, including the heparan sulfate-antithrombin system. Antithrombin III stimulates prostacyclin generation in endothelial cells by interacting with heparan sulfate of endothelial cells and inhibits cytokine and tissue factor production in endothelial cells and monocytes. Similar mechanisms may be involved in cellular actions of antithrombin III causing desensitization of chemoattractant receptors of leukocytes by activating the heparan sulfate proteoglycan, syndecan-4. Thus, antithrombin III might be among the useful agents for treating coagulation abnormalities associated with sepsis or other inflammation because it inhibits not only coagulation but also downregulation of anticoagulant activities of endothelial cells and affects leukocyte activation.