ALBERT

Description: Author(s): J. L. Aragones, L. G. MacDowell, J. I. Siepmann, and C. Vega [Phys. Rev. Lett. 107, 155702] Published Mon Oct 03, 2011

Description: Recent astrophysical observations have shown that some stars have sufficiently high carbon to oxygen ratios and may host planets composed mainly of carbides instead of silicates and oxides. From the low thermal expansion of SiC at 1 bar, it can be inferred that the buoyancy force of thermal anomalies is much lower in the carbide planets than in the silicate planets. However, numerous studies have shown that high pressure in planetary interiors can fundamentally change the physical properties of materials. We have measured the pressure–volume–temperature relations of two SiC polymorphs (3C and 6H) at pressures and temperatures up to 80 GPa and 1900 K and 65 GPa and 1920 K, respectively, in the laser-heated diamond anvil cell combined with synchrotron X-ray diffraction. We found no evidence of dissociations of these phases up to our maximum pressure condition, supporting the stability of SiC to 1900 km depth in Earth-size Si-rich carbide planets. Following the Mie-Grüneisen approach, we fit our data to the Birch-Murnaghan or the Vinet equations of state combined with the Debye approach. We found that the pressure induced change in the thermal expansion parameter of SiC is much smaller than that of Mg-silicate perovskite (bridgmanite). Our new measurements suggest that the thermal buoyancy force may be stronger in the deep interiors of Si-rich carbide exoplanets than in the “Earth-like” silicate planets.

Description: Recombinant erythropoietins are used extensively in the management of anemia associated with chronic kidney disease (CKD). All the currently available erythropoietins are synthesized in Chinese hamster ovary (CHO) cell lines resulting in differences in glycosylation compared with human serum erythropoietin. We report the molecular characterization and pharmacokinetic properties of epoetin delta (Dynepo®, Shire plc), the only erythropoietin produced in a human cell line. A variety of techniques have been used to characterize epoetin delta, including amino acid sequencing, peptide mapping with reverse-phase HPLC/mass spectrometry, oligosaccharide profiling and MALDI-TOF of released glycans. Sialic acid and N-glycolylneuraminic acid (Neu5Gc) residues were quantified, following labeling of the released glycans, by reverse-phase HPLC analysis with fluorescence detection. Epoetin delta was produced as a highly pure and stable protein with the full human primary amino acid sequence. Neu5Gc residues were not detectable in epoetin delta within the validated limits of the assay but became readily detectable in CHO derived epoetins. Following characterization of the molecule early studies were done to determine the pharmacokinetic and pharmacodynamic properties of epoetin delta. Two studies investigated responses to epoetin delta in healthy individuals. The first study involved randomization of 21 men to either intravenous (i.v.) epoetin delta (15, 40 or 100 IU/kg) or placebo. The second was an open-label, crossover study, involving 32 volunteers randomized to receive single doses of epoetin delta 75 IU/kg given i.v. or subcutaneous (s.c.) by injection. Two further studies were carried out with CKD patients requiring hemodialysis who had previously received epoetin alfa. The first involved 40 patients randomized to epoetin delta or epoetin alfa (50 or 100 IU/kg), three-times per week for 4 weeks. The second was a single-dose study in 28 patients comparing epoetin delta 150 and 300 IU/kg given i.v. or s.c. Pharmacokinetic parameters were calculated from serum erythropoietin concentrations (determined by ELISA) by validated non-compartmental techniques using WinNonlin Professional v3.0A. Intravenous epoetin delta in healthy individuals displayed non-linear and dose-dependent pharmacokinetics, with a dose-dependent effect on serum hemoglobin. The bioavailability of s.c. epoetin delta is around 30%, and concentrations peak later and decline more slowly than with i.v. injection. In hemodialysis patients pharmacokinetic parameters were similar to those in healthy individuals, although AUC and half-life were increased. Compared with the 50 IU/kg dose, treatment with epoetin delta 100 IU/kg was associated with a trend to increased hemoglobin and hematocrit levels. Epoetin delta was well tolerated in all participants with the frequency of adverse events occurring in dialysis patients as expected for that population. Adverse events were similar with epoetin alfa and epoetin delta. No neutralizing anti-erythropoietin antibodies were detected in any patient. Epoetin delta was characterized at the molecular level and levels of Neu5Gc residues were undetectable within the validated limits of the assay. The pharmacokinetic profile of epoetin delta and effects on hemoglobin and hematocrit levels were suitable for the treatment of anemia in CKD patients by either s.c or i.v. administration.