Four-hour Intravenous Infusion Research Articles

Safety, pharmacokinetics and pharmacodynamics of four-hour intravenous infusions of eritoran in healthy Japanese and Caucasian men

Eritoran, a synthetic analogue of lipid A, has been shown to bind to TLR4/MD-2 complex and thereby block the interaction of endotoxins with TLR4. We report here the results of a study conducted to assess the single-dose safety and tolerability, as well as the pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult men. Sixty-four men (aged 20-45 years; body mass index 18-30 kg/m(2)) were randomized into four groups: 4-mg total dose (six Japanese and six Caucasian men); 12-mg total dose (12 Japanese and 12 Caucasian men); 28-mg total dose (six Japanese and six Caucasian men); and placebo (eight Japanese and eight Caucasian men). Eritoran in single doses up to 28 mg over 4 h was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher in Japanese versus Caucasian men; these differences were not significant after adjustment for differences in body mass (clearance: approximately 1.2 ml/h/kg; volume of distribution at steady state: approximately 0.07 l/kg). The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian men. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.

Cerebral net exchange of Brain-Derived Neurotrophic Factor (BDNF) during experimental systemic inflammation and hypoxaemia in humans

Sepsis is notably associated with neuronal damage, an effect that may be exacerbated by hypoxaemia. The present study was designed to investigate if this interrelationship involves an effect on brain-derived neurotrophic factor (BDNF), an intrinsic neuroprotective agent which is released from the brain under normophysiological conditions [1]. We hypothesised that experimental systemic inflammation and hypoxaemia would abolish this release. 36 healthy male volunteers aged 25 (SD, 4) years were randomised to: 1. normoxia for 12 hours and a four-hour intravenous infusion of lipopolysaccharide (LPS) from 4–8 h (total dose 0.3 ng/kg), N = 12 2. hypoxia for 12 hours (12.9% O2) and a four-hour intravenous infusion of saline from 4–8 h, N = 11 3. hypoxia for 12 hours (12.9% O2) and a four-hour intravenous infusion of LPS from 4–8 h (total dose of 0.3 ng/kg), N = 13 Cerebral blood flow (CBF) was measured by the Kety-Schmidt technique, and arterio-jugular venous concentrations of BDNF were determined at baseline and 9 h. The cerebral net exchange was calculated by multiplying CBF with the arterio-jugular concentration differences of BDNF. A cerebral release of BDNF was present at baseline (P < 0.005). This was attenuated in all three groups, but with no difference in the cerebral net exchange values from baseline or between interventions (NS, MANOVA). There was no effect of any of the interventions on the arterial levels of BDNF (NS, MANOVA). In conclusion, systemic inflammation and hypoxaemia may abolish the net cerebral release of BDNF in healthy humans.

Effect of a 15-Minute Infusion of DDAVP on the Pharmacokinetics and Pharmacodynamics of ™REVASC during a Four-Hour Intravenous Infusion in Healthy Male Volunteers

Plasma pharmacokinetics, effect on coagulation parameters, and safety and tolerability of an intravenous infusion of REVASC before, during and after a DDAVP infusion were investigated. Twelve healthy volunteers were given an intravenous bolus dose followed by a constant rate four-hour infusion of REVASC. Fifteen-minute infusions of 0.9% saline and DDAVP were started two and three hours respectively after the start of the REVASC infusion. Plasma REVASC concentrations were not affected by either the saline or DDAVP infusion. REVASC infusion produced an increase in APTT which plateaued between 0.5 and 3 hours. After the DDAVP infusion there was a tendency towards a new lower plateau whilst the REVASC infusion continued. There were no serious adverse events or bleeding episodes throughout the study. In conclusion, the co-administration of intravenous DDAVP has no effect on the plasma pharmacokinetics of REVASC and partially reverses the REVASC-induced increase in APTT. This may represent a role for DDAVP in the partial reversal of anticoagulation induced by REVASC.

Phase I/II study of recombinant human granulocyte-macrophage colony- stimulating factor in aplastic anemia and myelodysplastic syndrome

We performed a phase I/II study of the administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with aplastic anemia or myelodysplastic syndrome. Doses ranging from 15 to 480 micrograms/m2 were administered as a one-hour or four-hour intravenous infusion daily for 7 days or as a 12-hour infusion for 14 days. Temporary improvements were seen in granulocyte counts, monocyte counts, and reticulocyte counts in six of eight patients with aplastic anemia and five of seven patients with myelodysplastic syndromes. The patients with myelodysplastic syndromes had larger increases in granulocyte, monocyte, and reticulocyte counts than did those with aplastic anemia, and they also had increases in the numbers of eosinophils (two of seven), immature myeloid cells (two of seven), and myeloblasts (two of seven) that were not observed in patients with aplastic anemia. There was no reduction in erythrocyte transfusion requirements, and no effect was observed on platelet counts. There was only minimal toxicity consisting of transient low- back discomfort, anorexia, myalgias/arthralgias, and low-grade fever. Our data suggest that GM-CSF is well tolerated and is more likely to result in elevations of blood counts in patients with myelodysplasia than in patients with aplastic anemia, but the role of GM-CSF therapy in these disorders remains to be determined.

Phase I/II Study of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor in Aplastic Anemia and Myelodysplastic Syndrome

We performed a phase I/II study of the administration of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with aplastic anemia or myelodysplastic syndrome. Doses ranging from 15 to 480 micrograms/m2 were administered as a one-hour or four-hour intravenous infusion daily for 7 days or as a 12-hour infusion for 14 days. Temporary improvements were seen in granulocyte counts, monocyte counts, and reticulocyte counts in six of eight patients with aplastic anemia and five of seven patients with myelodysplastic syndromes. The patients with myelodysplastic syndromes had larger increases in granulocyte, monocyte, and reticulocyte counts than did those with aplastic anemia, and they also had increases in the numbers of eosinophils (two of seven), immature myeloid cells (two of seven), and myeloblasts (two of seven) that were not observed in patients with aplastic anemia. There was no reduction in erythrocyte transfusion requirements, and no effect was observed on platelet counts. There was only minimal toxicity consisting of transient low-back discomfort, anorexia, myalgias/arthralgias, and low-grade fever. Our data suggest that GM-CSF is well tolerated and is more likely to result in elevations of blood counts in patients with myelodysplasia than in patients with aplastic anemia, but the role of GM-CSF therapy in these disorders remains to be determined.

A simple and reliable test for the diagnosis of hyperparathyroidism

Factors affecting the level of urinary excretion of phosphorus following a four-hour intravenous infusion of calcium were examined. Changes in amount of urinary phosphorus excretion during the second half of the calcium infusion day, were compared to those of the corresponding period of the control day in 20 patients with hyperparathyroidism and 22 normal subjects. Responses to calcium infusion differed in the two groups of subjects. In normal patients phosphorus excretion was decreased by > 29%, in hyperparathyroid patients by

A Simple and Reliable Test for the Diagnosis of Hyperparathyroidism

Factors affecting the level of urinary excretion of phosphorus following a four-hour intravenous infusion of calcium were examined. Changes in amount of urinary phosphorus excretion during the second half of the calcium infusion day, were compared to those of the corresponding period of the control day in 20 patients with hyperparathyroidism and 22 normal subjects. Responses to calcium infusion differed in the two groups of subjects. In normal patients phosphorus excretion was decreased by > 29%, in hyperparathyroid patients by