Systemic upregulation of leukocyte integrins in response to lower body ischemia-reperfusion during abdominal aortic aneurysm repair.

Ischemia and reperfusion in myocardial infarction and stroke are associated with upregulation of leukocyte adhesion molecules, which contributes to tissue injury by facilitating leukocyte adhesion and infiltration in the affected tissues. Surgical repair of the abdominal aortic aneurysm involves clamping and declamping of the aorta, which necessarily results in ischemia and reperfusion of the lower half of the body. Given the large volume of the affected tissues and unimpeded venous return during reperfusion, we hypothesized that the procedure may result in upregulation of leukocyte integrins in the systemic circulation. To test this hypothesis, we studied neutrophil and monocyte surface densities of CD11b and CD18 in patients undergoing elective infrarenal abdominal aortic aneurysm repair. Serial blood samples were collected from the radial artery and femoral vein during the operation and leukocyte CD11b and CD18 surface densities were quantified by flow cytometry. Following reperfusion, CD11b expression in neutrophils and monocytes increased significantly in femoral venous and arterial blood. The mean time to peak expression of CD11 b in neutrophils and monocytes during reperfusion was 34.4 and 31.4 minutes in venous and 38.5 and 36.4 minutes in arterial blood, respectively. Similar rises in CD18 expression on neutrophils and monocytes were observed in venous and arterial blood. The mean time to peak expression of CD18 in neutrophils and monocytes during reperfusion was 34.0 and 40.0 minutes in venous and 47.5 and 50.0 minutes in arterial blood, respectively.

Pharmacokinetics and pharmacodynamics of darbepoetin alfa and epoetin in patients undergoing dialysis.

OBJECTIVE: The aim of this multicenter, randomized, open-label study was to compare the pharmacokinetic and pharmacodynamic profiles of darbepoetin alfa, a new erythropoiesis-stimulating protein, and recombinant human erythropoietin (epoetin) after repeated intravenous dosing in patients with chronic kidney disease receiving hemodialysis. METHODS: Forty-seven patients were randomized to receive darbepoetin alfa administered once weekly (n = 17) or 3 times weekly (n = 15) or epoetin administered 3 times weekly (n = 15) for up to 52 weeks. Pharmacokinetic profiles were measured during weeks 1 and 12 and at hemoglobin steady state (defined as a hemoglobin concentration within the target range for 4 consecutive weeks after week 12 with no change in study drug dose) or between weeks 36 and 40, whichever occurred first. RESULTS: At each of the 3 time points evaluated, the terminal half-life of darbepoetin alfa was 2 to 3 times longer and the clearance approximately 4 times slower than those of epoetin. At week 12, the terminal half-life was 23.4 hours with darbepoetin alfa once weekly, 18.3 hours with darbepoetin alfa 3 times weekly, and 8.0 hours with epoetin 3 times weekly. The pharmacokinetics of darbepoetin alfa was not dependent on dose or time. Mean hemoglobin values at steady state were all approximately 11 g/dL, within the target range of 9.0 to 13.0 g/dL. Safety analyses revealed no differences between darbepoetin alfa and epoetin. CONCLUSIONS: The pharmacokinetic and pharmacodynamic profiles and safety data for darbepoetin alfa demonstrate that it can be administered less frequently than epoetin in patients with chronic kidney disease receiving hemodialysis, thus simplifying anemia management.