Modulation of calcification of vascular smooth muscle cells in culture by calcium antagonists, statins, and their combination

Background Vascular calcification is an organized process in which vascular smooth muscle cells (VSMCs) are implicated primarily. The purpose of the present study was to assess the effects of calcium antagonists and statins on VSMC calcification in vitro. Methods VSMC calcification was stimulated by incubation in growth medium supplemented with 10 mmol/l β-glycerophosphate, 8 mmol/l CaCl2, 10 mmol/l sodium pyruvate, 1 μmol/l insulin, 50 μg/ml ascorbic acid, and 100 nmol/l dexamethasone (calcification medium). Calcification, proliferation, and apoptosis of VSMCs were quantified. Results Calcium deposition was stimulated dose-dependently by β-glycerophosphate, CaCl2, and ascorbic acid (all P < 0.01). Addition of amlodipine (0.01–1 μmol/l) to the calcification medium did not affect VSMC calcification. However, atorvastatin (2–50 μmol/l) stimulated calcium deposition dose-dependently. Combining treatments stimulated calcification to a degree similar to that observed with atorvastatin alone. Both atorvastatin and amlodipine inhibited VSMC proliferation at the highest concentration used. Only atorvastatin (50 μmol/l) induced considerable apoptosis of VSMCs. Conclusion In vitro calcification of VSMCs is not affected by amlodipine, but is stimulated by atorvastatin at concentrations ≥10 μmol/l, which could contribute to the plaque-stabilizing effect reported for statins

alpha- and beta-homogalactonojirimycins (alpha- and beta-homogalactostatins): Synthesis and further biological evaluation

The homoiminosugars alpha- and beta -homogalactonojirimycins were prepared from a common intermediate, tetra-O-benzyl-D-galacto-heptenitol 6, by way of highly stereoselective reaction sequences involving, as the key steps, an internal amidomercuralion (a-epimer) and a double reductive amination (beta -epimer). alpha -Homogalactonojirimycin retains a large part of the potent activity of the parent galactonojirimycin and 1-deoxygalactonojirimycin as an inhibitor of alpha -galaclosidases. However, by contrast with the parent iminosugars, it does not inhibit beta -galactosidases, with the exception of the Jack beans enzyme. beta -Homogalactonojirimycin is a weak cc-galactosidase inhibitor and is completely devoid of activity towards P-galactosidases. Thus, a marked selectivity toward one family of enzymes has been achieved by the addition of an alpha -CH2OH group in the structure of the parent iminosugars. (C) 2001 Elsevier Science Ltd. All rights reserved

Pharmacokinetics and skin-tissue penetration of daptomycin in rats

Kazuaki Matsumoto,1 Masashi Kitaoka,1 Yuko Kuroda,1 Kazuro Ikawa,2 Norifumi Morikawa,2 Junichi Sasaki,3 Osamu Iketani,4 Satoshi Iwata,4 Tetsuya Horino,5 Seiji Hori,5 Junko Kizu1 1Division of Practical Pharmacy, Keio University Faculty of Pharmacy, Tokyo, 2Department of Clinical Pharmacotherapy, Hiroshima University, Hiroshima, 3Department of Emergency and Critical Care Medicine, 4Center for Infectious Diseases and Infection Control, Keio University School of Medicine, 5Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Tokyo, Japan Background: Daptomycin is recommended for complicated skin and skin-structure infections. However, information on the penetration of daptomycin into skin is limited. Therefore, the aim of this in vivo investigation was to determine the pharmacokinetics and skin penetration of daptomycin in rats. Materials and methods: Concentrations of daptomycin were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was conducted to estimate the rate and extent of daptomycin penetration from the systemic circulation into skin tissue. Since protein binding of daptomycin in rat serum was 89.3%, the free maximum concentration (Cmax) and free area under the curve from time 0 to infinity (AUC0&ndash;&infin;) for plasma were calculated as follows: fCmax, plasma = (1 &ndash; 0.893) &times; Cmax, plasma, fAUC0&ndash;&infin;, plasma = (1 &ndash; 0.893) &times; AUC0&ndash;&infin;, plasma. Results: The following values (mean &plusmn; standard deviation) were obtained: 0.06&plusmn;0 L/h/kg for total clearance (CLtotal), 0.44&plusmn;0.06 hours for elimination-rate constant, 1.58&plusmn;0.23 hours for half-life, 0.14&plusmn;0.02 L/kg for steady-state volume distribution, and 2.28&plusmn;0.33 hours for mean residence time. Time to Cmax was 3.0 hours for plasma and skin tissue. Cmax and AUC0&ndash;&infin; for plasma were 175.8&plusmn;5.1 &micro;g/mL and 811.8&plusmn;31.9 &micro;g &times; h/mL, respectively. Cmax and AUC0&ndash;&infin; for skin tissue were 19.1&plusmn;1.7 &micro;g/mL and 113.9&plusmn;21.8 &micro;g &times; h/mL, respectively. Furthermore, fCmax and fAUC0&ndash;&infin; for plasma were 18.8 &micro;g/mL and 86.9 &micro;g &times; h/mL, respectively. The degrees of skin-tissue penetration, defined as the Cmax, skin tissue/fCmax, plasma ratio and AUC0&ndash;&infin;, skin tissue/fAUC0&ndash;&infin;, plasma ratio, were 1.0 and 1.3, respectively. Conclusion: Daptomycin exhibited good penetration into skin tissue, supporting its use for the treatment of complicated skin and skin-structure infections. However, further studies are needed in infected patients in order to investigate the relationship between the antimicrobial efficacy of daptomycin and its drug concentrations in skin tissues. Keywords: daptomycin, pharmacokinetics, rat, skin-tissue penetratio

World War II (1939-1945) Oceanographic Observations

We document the geographical and temporal distributions of oceanographic vertical profile observations made during World War II (1939-1945) that are included in the " World Ocean Database " (WOD). The WOD is a product of the NOAA/National Oceanographic Data Center, USA and its co-located ICSU World Data Center for Oceanography. The WOD is the largest collection of ocean profile data available internationally without restriction. All data shown in this paper are available online without restriction and at no cost. The WOD is built upon the international exchange of oceanographic data with contributions of data received from many countries. Most of the data shown in this paper and the data within the WOD in which these data reside in a uniform format were gathered under the auspices of the International Oceanographic Data and Information Exchange (IODE) committee of the Intergovernmental Oceanographic Commission (IOC) of UNESCO and the ICSU (International Council of Science) World Data Center system, which is now part of the ICSU World Data System. The WOD contains 112,714 ocean station data casts and 45,003 mechanical bathythermograph profiles for 1939-194