Pharmaceutical development of a parenteral lyophilized formulation of the investigational polymer-conjugated platinum anticancer agent AP 5280

AP 5280 is a novel polymer-conjugated platinum anticancer agent showing promising in vitro and in vivo activity against solid tumors. The aim of this study was to develop a parenteral pharmaceutical dosage form for phase I clinical trials. AP 5280 drug substance was characterized by using a wide range of analytical techniques and showed excellent solubility in water. However, as aqueous solutions of AP 5280 proved to be labile upon sterilization by moist heat, it was decided to develop a lyophilized dosage form. Initially, glass vials were used as primary packaging, but this led to a high breakage rate, which could be completely prevented by the use of CZ® resin vials. Stability studies to date show that the lyophilized product in glass vials is stable for at least 12 months when stored at 2-8°C in the dark and the lyophilized product in CZ resin vials is stable for at least 6 months under these conditions. Photostability testing revealed photolability of AP 5280 drug substance and lyophilized product in both types of primary container, necessitating storage in the dark. The first clinical experiences indicate that the proposed formulation is fully applicable for use in the clinical setting.     

Estimation of genetic parameters for concentrations of milk urea nitrogen

The objective of this study was to use field data collected by dairy herd improvement programs to estimate genetic parameters for concentrations of milk urea nitrogen (MUN). Edited data were 36,074 test-day records of MUN and yields of milk, fat, and protein obtained from 6102 cows in Holstein herds in Ontario, Canada. Data were divided into three sets, for the first three lactations. Two analyses were performed on data from each lactation. The first procedure used ANOVA to estimate the significance of the effects of several environmental factors on MUN. Herd-test-day effects had the most significant impact on MUN. Effects of stage of lactation were also important, and MUN levels tended to increase from the time of peak yield until the end of lactation. The second analysis used a random regression model to estimate heritabilities and genetic correlations of MUN and the yield traits. Heritability estimates for MUN in lactations one, two, and three were 0.44, 0.59, and 0.48, respectively. Heritabilities for the yield traits were of a similar magnitude. Little relationship was observed between MUN and yield. Raw phenotypic correlations were all <0.10 (absolute value). Genetic correlations with production traits were close to zero in lactations one and three and only slightly positive in lactation two. The results indicate that selection on MUN is possible, but relationships between MUN and other economically important traits such as metabolic disease and fertility are needed.     

Comparison of diffusive gradients in thin films and equilibrium dialysis for the determination of Al, Fe(III) and Zn complexed with dissolved organic matter

The distinction between 'free' metals and organically complexed metals in aqueous solutions is important for research involving the mobility or bioavailability of metals in the environment. In this study, the applicability of equilibrium dialysis (molecular weight cut-off = 1000 Da) and diffusive gradients in thin films (DGT) to determine 'free' Al, Fe(III) and Zn in four forest soil solutions was compared. The 'free' metals as measured by both methods, consist of hydrated metal cations and soluble inorganic metal complexes. In addition, dialysis measures any organic complexes < 1000 Da and DGT measures a portion of smaller labile organic complexes. The four soil solutions were prepared by water extraction of an organic soil horizon (H) from a Fimic Anthrosol, and contained either 20 or 75 mg C/l dissolved organic matter at pH 4.0 and pH 7.0. To test the performance of both methods and optimize experimental volume and time, experiments using metal nitrate solutions were carried out. In the solutions at pH 4.0, no significant differences in average 'free' metal contents were found for Al, Fe(III) or Zn. This makes DGT a viable alternative for equilibrium dialysis for the study of the complexation of all three metals in acidic soils. At pH 7.0, again no significant difference between both methods were found for Al and Fe(III), but the DGT results for Zn were significantly higher. This was likely caused by labile organic complexes that were only detected by DGT.     

Monkman-grant analysis of creep fracture in dispersion-strengthened and particulate-reinforced aluminum

The tensile creep fracture properties of coarse- and fine-grained dispersion-strengthened-cast aluminum (DSC-Al) with 25 vol pct of submicron alumina dispersoids are presented for temperatures between 335 °C and 500 °C and stresses between 30 and 100 MPa. The primary, secondary, and tertiary creep strains are analyzed in terms of the minimum creep rate, applied stress, and temperature. Good agreement with the original and the modified Monkman-Grant relationships is found for the failure time of DSC-Al and other aluminum materials reinforced with dispersoids or particulates. The origin of the Monkman-Grant relationships for these materials is discussed in terms of stress exponents, specific interfacial areas, and ratio of secondary strain to failure strain.     

Phase Relations in the Bi–Sr–Ca–Cu–M–O (M = Y, Dy, Ho, Er, Tm, Yb, Lu) Systems

The phase relations in the Bi–Sr–Ca–Cu–M–O (M = Y, Dy, Ho, Er, Tm, Yb, Lu) systems near Bi₂Sr₂CaCu₂O_{8+ x} (Bi-2212) were studied between 850 and 990°C. The results demonstrate that larger sized rare earths (Y, Dy, Ho, Er) substitute on the Ca site in Bi-2212, leading to the formation of CaO. Smaller sized rare earths (Tm, Yb, Lu) replace lesser amounts of Ca and form Sr₂MBiO₆phases. In the material of nominal composition Bi₂Sr₂Ca_0.85M_0.15Cu₂O_{8 + x} + 0.25Sr₂YBiO₆prepared via melt processing, a major fraction of the Y atoms substitute for Ca in Bi-2212, resulting in a low-T _cmultiphase superconductor. In the analogous Yb system, a Bi-2212–Sr₂YbBiO₆composite with T _c= 87 K is obtained.     

Mental health policy: Observations from Europe.

Reviews policies and practices based on a study of 5 European countries (Switzerland, England, Denmark, Sweden, and the Netherlands) with respect to deinstitutionalization and community support and rehabilitation services, health and social security benefits, financing mechanisms, and care for the homeless and young adult chronic populations. Common trends in European mental health and social welfare policies are summarized. Relative to the US, the coordinated system of care in these countries is supported by a strong social welfare system allowing for community-based care administered by the mental health service system. (19 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Maltose hydrolysis kinetics with glucoamylase immobilized in porous glass fibers in a tubular flow reactor

Glucoamylase has been covalently immobilized in controlled pore glass fibers packed parallel to the axis of a tubular reactor. Flow kinetic studies have been carried out for a range of flow rates and substrate concentrations at 50°C and pH 4.5. Diffusion control has been found negligible with high flow rates and substrate concentrations. The apparent Michaelis constant was three orders of magnitude higher than that of the free enzyme. As flow rate and substrate concentration decrease, the extent of diffusion control increased up to a moderate degree. The immobilized glucoamylase was more stable than the free enzyme when incubated at 50°C.     

Accelerant‐promoted free radical polymerization of methacrylates by stabilized nitroxide unimolecular initiators: synthesis and characterization

BACKGROUND: This investigation evaluates the effectiveness of initiator adducts for living and controlled polymerization of methacrylates, crosslinking of dimethacrylates and thermal stabilities of the resulting polymers. Adducts of 2,2,6,6‐tetramethyl‐1‐piperidinyloxy with benzoyl peroxide and with azobisisobutyronitrile were prepared and evaluated as stabilized unimolecular initiators for the free radical polymerization of methacrylate monomers using sulfuric acid as catalyst. The monomers used were methyl methacrylate, triethylene glycol dimethacrylate (TEGDMA) and ethoxylated bisphenol A dimethacrylate (EBPADMA). RESULTS: Successful polymerization was achieved at 70 and 130 °C with reaction times ranging from 45 min to 120 h. The dispersity (D) of poly(methyl methacrylate) (PMMA) was 1.09–1.28. The livingness and extent of control over polymerization were confirmed with plots of M_n evolution as a function of monomer conversion and of the first‐order kinetics. The glass transition temperature (T_g) for PMMA was 123–128 °C. The degradation temperature (T_d) for PMMA was 350–410 °C. T_d for poly(TEGMA) was 250–310 °C and for poly(EBPADMA) was 320–390 °C. CONCLUSION: The initiators are suitable for free radical living and controlled polymerization of methacrylates and dimethacrylates under mild thermal and acid‐catalyzed conditions, yielding medium to high molecular weight polymers with low dispersity, high crosslinking and good thermal stability. Copyright © 2008 Society of Chemical Industry     

The effect of silicide on ESD performance of transistors

In this paper a new model for localized breakdown in NMOSTs under ESD stress is developed, which accounts for the reduced ESD strength in silicided devices. The model explains the impact of a stabilizing drain resistance on second breakdown current for both silicided and unsilicided protections.