Aprotinin decreases release of 6-keto-prostaglandin F1 alpha and increases release of thromboxane B2 in cultured human umbilical vein endothelial cells.

Use of the proteinase inhibitor aprotinin significantly improves hemostasis and reduces bleeding after operations in which extracorporeal circulation is used. The mechanism of action, however, has been only partially clarified. In this work we investigated whether aprotinin influenced the production and release of the eicosanoids prostacyclin, measured as the stable metabolite 6-keto-prostaglandin F1 alpha, and thromboxane A2, measured as the stable metabolite thromboxane B2, from endothelial cells. Human umbilical vein endothelial cells were incubated with different concentrations of aprotinin (5.5, 20, 55, and 100 mumol/L). The levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 were measured at baseline and after thrombin stimulation. A concentration-dependent effect of aprotinin on 6-keto-prostaglandin F1 alpha synthesis was demonstrated. After incubation with 100 mumol/L of aprotinin, a 90% reduction in 6-keto-prostaglandin F1 alpha production was seen (31.69 versus 307.44 picograms per million cells; p less than 0.001). Conversely, thromboxane B2 production showed a 345% increase after incubation with aprotinin (287.80 versus 83.82 picograms per million cells; p less than 0.0001). Since 6-keto-prostaglandin F1 alpha inhibits and thromboxane B2 strongly enhances platelet aggregation, it appears that one mechanism of the clinically observed effectiveness of aprotinin lies in the altered ratio of 6-keto-prostaglandin F1 alpha: thromboxane B2 in endothelial cells, which leads to enhanced platelet aggregation and improved vessel sealing.

Aprotinin increases release of von Willebrand factor in cultured human umbilical vein endothelial cells.

Through the perioperative administration of the proteinase inhibitor aprotinin, hemostasis can be improved and postoperative bleeding reduced after cardiac operations. The mechanism of action has been only partially clarified. The goal of our study was to investigate the influence of aprotinin on the synthesis of von Willebrand factor (vWF) in human endothelial cells. Human umbilical vein endothelial cells (HUVEC) were cultivated in vitro and incubated with different aprotinin concentrations (55, 100, and 215 mol/L). With all investigated aprotinin concentrations, there was an increase in vWF synthesis compared with basal secretion (p less than 0.001). When the HUVEC were preincubated with aprotinin and stimulated with thrombin, there was a further significant increase in vWF synthesis. HUVEC that, were first incubated with aprotinin and then stimulated with thrombin demonstrated a significant increase in vWF synthesis compared with basal secretion in nonincubated cells (p less than 0.0001). Also, compared with the cells that had received thrombin stimulation alone, the combination of aprotinin incubation and thrombin stimulation led to a significantly higher vWF concentration (p less than 0.05). Because vWF is necessary for the interaction with platelet factor glycoprotein Ib and platelet adhesion, the demonstrated increase in vWF synthesis could be one of the mechanisms of action of aprotinin leading to its blood-sparing effect.

Prophylactic use of hyperimmunoglobulin for cytomegalovirus infection in heart transplantation.

Cytomegalovirus (CMV) infection in solid organ recipients can endanger the immunosuppressed patient and increase vulnerability to secondary infections and the high risk of rejection triggered by the viral disease. The effect of passive immunization against CMV was examined in 69 heart transplant patients. The patients received weekly administrations of 1 ml/kg of CMV hyperimmunoglobulin from the day of transplantation until the 30th postoperative day. Forty-four of the patients were monitored clinically and serologically up to the 120th postoperative day. Nine patients showed clinical and serologic signs of CMV infection; in 15 the only evidence of CMV infection was a rise in antibody titers. The remaining 20 patients showed no clinical or serologic signs of CMV infection. Three patients who were seronegative preoperatively remained seronegative until the end of the observation period. The results indicate a potential therapeutic benefit of hyperimmunoglobulin prophylaxis to prevent infectious complications due to CMV in heart transplant patients.

Effect of cefotaxime, ceftriaxone and latamoxef on blood coagulation in patients on parenteral nutrition.

Plasmatic coagulation parameters were studied in patients on parenteral cephalosporins with different hepatic pharmacokinetics. Sixty patients received either cefotaxime (4 g/day), ceftriaxone (2 g/day) or latamoxef (4 g/day) pre- and postoperatively for at least 5 days at random. They received parenteral nutrition without vitamin K supply and had no oral intake. A significant drop (p less than 0.05) in vitamin-K-dependent coagulation factors was recorded in patients treated with latamoxef, while patients receiving ceftriaxone and cefotaxime did not exhibit a significant change in their plasmatic coagulation parameters. Interference of some cephalosporins with the vitamin-K-dependent hepatic metabolism of clotting factors seems to be likely, rather than a suppression of intestinal vitamin K production by the intestinal microflora.

[Biochemical changes in skeletal muscles after chronic indirect stimulation]. / Biochemische Veränderungen in Skelettmuskulatur nach chronischer indirekter Stimulation.

The skeletal muscle has the capacity to respond adaptively to increased use. This observation could open up the feasibility of constructing pumping chambers to support or even replace cardiac work. We investigated the changes in enzyme activity due to chronic stimulation in an animal skeletal muscle. In 5 adult sheep the psoas muscle of one side was electrically stimulated through the muscle nerves, with an implantable stimulation unit for 5 weeks. The activity of the hexokinase (E.C.2.7.1.1.), lactate dehydrogenase (E.C.1.1.1.27), malate dehydrogenase (E.C.1.1.1.37), creatine kinase (E.C.2.7.3.2.) choline acetyltransferase and the contents of adenosine triphosphate and adenosine diphosphate were determined in bioptic specimen. The use of only 15 Hertz as a stimulation frequency led to a transformation of an originally fast-twitch muscle into a slow-twitch muscle with reduced susceptibility to fatigue. These results indicate a potential role of the skeletal muscle as an ideal myocardial substitute with the ability to perform hemodynamic work.