Ceruloplasmin deletion in myelinating glial cells induces myelin disruption and oxidative stress in the central and peripheral nervous systems.

Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux and has been postulated to have a neuroprotective role. During the myelination process, oligodendrocytes (OLs) and Schwann cells (SCs) express high levels of Cp, but the role of this enzyme in glial cell development and function is completely unknown. To define the function of Cp in the myelination of the central and peripheral nervous systems, we have conditionally knocked-out Cp specifically in OLs and SCs during early postnatal development as well as in aged mice. Cp ablation in early OLs (postnatal day 2, P2) significantly affects the differentiation of these cells and the synthesis of myelin through the first four postnatal weeks. The total number of mature myelinating OLs was reduced, and the density of apoptotic OLs was increased. These changes were accompanied with reductions in the percentage of myelinated axons and increases in the g-ratio of myelinated fibers. Cp ablation in young myelinating OLs (P30 or P60) did not affect myelin synthesis and/or OL numbers, however, Cp loss in aged OLs (8 months) induced cell iron overload, apoptotic cell death, brain oxidative stress, neurodegeneration and myelin disruption. Furthermore, Cp deletion in SCs affected postnatal SC development and myelination and produced motor coordination deficits as well as oxidative stress in young and aged peripheral nerves. Together, our data indicate that Cp ferroxidase activity is essential for OLs and SCs maturation during early postnatal development and iron homeostasis in matured myelinating cells. Additionally, our results suggest that Cp expression in myelinating glial cells is crucial to prevent oxidative stress and neurodegeneration in the central and peripheral nervous systems.

The pharmacokinetics of single high doses of dexamethasone in cancer patients.

We have given single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin. The patients received graded doses of dexamethasone phosphate, in the range 40-200 mg, dependent upon nausea and vomiting scores, during up to three consecutive cycles of cancer chemotherapy. Plasma and urine concentrations of dexamethasone (dexamethasone alcohol) were measured by HPLC. The plasma concentration - time data were described by an open two-compartment model. The pharmacokinetic variables were independent of the dose of dexamethasone over the range studied. The terminal half-time was 4.0 +/- 0.4 h and the total body clearance was 3.5 +/- 0.4 ml X min-1 X kg-1. The volume of the central compartment and the total apparent volume of distribution were 0.23 +/- 0.03 and 1.0 +/- 0.1 l X kg-1 respectively. Approximately 8% of the dose was excreted into the urine as dexamethasone.

Single, high-dose intravenous dexamethasone as an antiemetic in cancer chemotherapy.

The antiemetic effect of graded, single high-dose intravenous dexamethasone was studied in 27 patients receiving combination chemotherapy with either doxorubicin (50 mg/m2) or cis-platinum (100 mg/m2). A total of 57 cycles were individually evaluated, utilizing a detailed rating system. Nausea and vomiting did not occur in 20 of 57 cycles; in 17, the chemotherapy was doxorubicin-based, and in 3 it was cis-platinum-based. Of the 37 cycles associated with nausea and vomiting, 32 contained cis-platinum and 5 doxorubicin. The average dexamethasone dosages for doxorubicin and platinum-containing combinations were 40 and 95 mg/m2, respectively. Side effects included a dose-dependent sensation of perineal pruritus (11 patients, 17 cycles) lasting for several minutes, and subjective feelings of increased appetite and well-being. Dexamethasone administered intravenously 15 min prior to chemotherapy in a dose of 40 mg/m2 apparently provides highly effective antiemetic protection for patients receiving treatment cycles containing doxorubicin; however, for patients receiving regimens containing cis-platinum, the antiemetic effect of dexamethasone as a single agent is limited.

The use of erythrocytes for delivery of chemotherapeutic agents to the reticuloendothelial system.

The object of our work is to define the possible role of hypotonically loaded erythrocytes as carriers to target drugs to the reticuloendothelial system. We have examined choices of drugs for loading into the erythrocytes and have considered methods of altering potentially useful agents so that they will load. We have demonstrated that the delivery of bleomycin to the reticuloendothelial system of mice, inside erythrocyte carriers, potentiates the effect of this drug on phagocytosis. We speculate, that this targeted delivery of bleomycin to phagocytes could be beneficial in the treatment of diseases characterized by an important phagocytic component.