bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Interface Roughness on Fiber Push‐Out Stress
Authors: Liu Hong‐Yuan , Zhou Li‐Min , Mai Yiu‐Wing
Published: September 2005

A theoretical analysis is given for single‐fiber push‐out with a rough interface whose asperity amplitude can be expressed by a Fourier series that has a good convergence. Based on a three‐cylinder model for the single‐fiber push‐out test, the solutions of the fiber frictional push‐out stress and the relative displacement of the fiber to the matrix at the fiber‐matrix interface are obtained. A new asperity wear model is introduced in the analysis to simulate the degradation of the asperity amplitude during the fiber push‐out process. The interfacial roughness between the fiber and the matrix is found to have a pronounced influence on the fiber sliding behavior.
Phase Equilibria in the Ti‐AI‐O System at 945°C and Analysis of Ti/Al2O3 Reactions
Authors: Kelkar Girish P. , Carim Altaf H.
Published: September 2005

Phase relations in the Ti‐Al‐O system were evaluated experimentally at 945°C. The tie lines were established using equilibrated samples with phase compositions determined by electron probe microanalysis. The phase relations were in agreement with previous estimates but the phase fields of α‐Ti[O,Al] and Ti3Al[O] were significantly different. The Ti3Al[O] phase has a maximum solubility of 22 at. % O, corresponding to a nominal stoichiometry of Ti3AlO, whereas the α‐Ti[O,Al] phase, at a maximum O solubility of 33.33 at. %, has a negligible amount of Al in solution. The disagreement between these results and previous studies was attributed to the differences in experimental techniques for sample preparation and analysis. The reported layer sequences at the Ti/Al2O3 interface were evaluated based on the ternary section and the corresponding O activity diagram. The layered interfaces were found to be stable, with the evolution of the reaction products governed by the thickness of the initial Ti layer and the O partial pressure in the ambient.
Preparation of Multication α‐SiAlON Containing Strontium
Authors: Hwang C. James , Susnitzky David W. , Beaman Donald R.
Published: September 2005

The possibility of having Sr as an interstitial metal cation in α‐SiAION has been investigated in two systems: a single‐cation system (Si3N4‐SrO‐AlN) and a multication system (Si3N4‐(Y2O3/SrO/CaO)‐AlN). It was found that Sr alone does not form α‐SiAlON and that Sr could only be accommodated in α ‐SiAION in conjunction with Y and Ca. The Sr content of α‐SiAION increased as the total content of (Y + Ca) increased and appeared to reach a limit at 0.5 at.%, or 0.15 atom per α‐SiAlON. Unexpectedly, some of the α‐SiAlON that contained (Sr + Y + Ca) was present as laths or fibers with the c‐axis perpendicular to the hot‐press direction.
Novel Method for Preparing Nickel/YSZ Cermet by a Vapor‐Phase Process
Authors: Ogumi Zempachi , Ioroi Tsutomu , Uchimoto Yoshiharu , Takehara Zen‐ichiro
Published: September 2005

A novel method for preparing a nickel/YSZ (yttria‐stabilized zirconia) cermet has been developed. In the present work, YSZ was deposited onto a substrate containing NiO as an oxygen source by allowing it to undergo a phase reaction in a vapor mixture of ZrCl4 and YCl3. In the initial stage of the reaction, a porous YSZ layer was deposited onto an NiO pellet by chemical vapor deposition (CVD). The porous layer became finer and more gas‐tight as the CVD reactions proceeded, and the process then changed from CVD to electrochemical vapor deposition (EVD), resulting in the growth of a dense YSZ layer on the NiO pellet.
Cyclic Fatigue of Ce‐TZP/AI2O3 Composites: Role of the Degradation of Transformation Zone Shielding
Authors: Tsai Jing‐Fong , Shetty Dinesh K.
Published: September 2005

The origin of cyclic fatigue in two Ce‐TZP/Al2O3 composites was investigated by (a) measurements of residual stresses in the transformation zones and crack‐tip stress intensities in in situ loaded compact specimens using microprobe Raman spectroscopy, (b) examination of the crack‐tip transformation zones by transmission electron microscopy, and (c) measurements of crack‐growth rates in cyclic fatigue and in sustained loading at 400°C, a temperature at which stress‐induced transformation of the tetragonal zirconia to the monoclinic polymorph was suppressed. Transformation zones formed during cyclic fatigue consistently showed lower compressive residual stresses and higher crack‐tip stress intensities than the zones formed in sustained loading. Transmission electron microscopy revealed monoclinic laths of smaller average twin spacing and of multiple types of lattice correspondence in the transformation zones of the fatigue specimens as compared to the sustained‐load specimens. Crack‐growth measurements at 400°C indicated a significant suppression of the cyclic fatigue effect in the absence of transformation plasticity. These results in combination pointed to degradation of transformation‐zone shielding as an important contributing cause of cyclic fatigue in Ce‐TZP/Al2O, composites. A more efficient accommodation of the transformation strains within the zones appears to be the underlying mechanism of the degradation of zone shielding in cyclic fatigue.
Early Stages of Composite Formation by Oxidation ofLiquid Aluminum Alloys
Authors: Salas Olimpia , Jayaram Vikram , Vlach Kenneth C. , Levi Carlos G. , Mehrabian Robert
Published: September 2005

Microstructure evolution during the early stages in the directed oxidation of molten Al‐Mg and Al‐Mg‐Si alloys was investigated to provide needed insight into the origins of the incubation period and its practical elimination by SiO2 additions. Oxidation experiments were performed primarily in thermogravimetric balances and microstructures were analyzed by optical and scanning electron microscopy. Continuous heating above the alloy liquidus produces first a thin MgO layer and then a brief rapid growth of a spinel + metal mixture within a temperature range which depends on the alloy Mg content and the heating rate. The initial rapid oxidation terminates abruptly with the formation of a dense spinel layer at the surface, leading to a long incubation period of negligible weight gain. The surface MgO regenerates in this regime, while the metal channels slowly advance upward by dissolution of the dense spinel, eventually reaching the MgO and inducing the formation of composite nodules. These consist initially of spinel + metal upon which the conventional A12O3+ metal growth starts after the Mg in the near‐surface alloy is depleted to a critical level. SiO2 surface additions promote composite nucleation by locally hindering surface passivation, acting as an O source for continued spinel growth, and modifying the local chemistry to facilitate the formation of A12O3.
Failure Modes of a Unidirectional Ultra‐High‐Modulus Carbon‐Fiber Carbon‐Matrix Composite
Authors: Zaldivar Rafael J. , Rellick Gerald S. , Yang Jenn‐Ming
Published: September 2005

The objective of this study was to observe the effects of various microstructural features on the in situ, room‐temperature tensile fracture behavior of an ultra‐high‐modulus, unidirectional carbon/carbon (C/C) composite as a function of processing heat‐treatment temperature (HTT) over the range of 1100° to 2750°C. An in situ SEM flexural stage was used to observe the interactions between the advancing crack tip and the microstructural features in the frontal process zone. Following the lowest HTT of 1100°C, failure is dominated by the well‐bonded brittle matrix; a tortuous crack path in the E130 fibers appears to contribute to a relatively high utilization of fiber strength in spite of this brittle‐matrix failure. Approximate calculations of the interfacial shear stress that might be generated by matrix shrinkage during pyrolysis of the polymer to carbon were compared to approximations of crack‐tip interfacial shear stresses (IFSS) using the Cook‐Gordon approach. The results suggest that the strong bonding in the 1100°C HTT composite cannot be accounted for by friction alone, and, therefore, chemical bonding or some type of fiber‐matrix mechanical interlocking must be involved. Higher HTTs lead to progressive weakening of the fiber‐matrix interface, and, with heat treatment to 2150°C, multiple matrix cracking (MMC) is observed. Using the crack‐spacing model of Aveston, Cooper, and Kelly (ACK), an IFSS of 1 MPa is estimated for the MMC case. Attempts to calculate the matrix failure strain using the ACK formulation led to a large overprediction of the failure strain, although a number of the parameters used in the calculation are known only very approximately. Heat treatments to 2400° and 2750°C led to longitudinal intramatrix cohesive failure; at 2750°C, this damage is extensive and results in composites with strength utilizations approaching those of dry fiber bundles.
Deformation Bands in Ceria‐Stabilized Tetragonal Zirconia/Alumina: I, Measurement of Internal Stresses
Authors: Sergo Valter , Clarke David R. , Pompe Wolfgang
Published: September 2005

The residual stresses within a deformation band in a ceriastabilized tetragonal zirconia/alumina (Ce‐TZP/Al2O3) ceramic composite are measured by piezo‐spectroscopy, in the zirconia phases from their Raman spectra and in the alumina phase from its Cr3+fluorescence. The concentrations of monoclinic zirconia across the deformation band are obtained from Raman spectra recorded from locations across the band. These measurements show that the deformation bands are associated with a localization of the tetragonal‐to‐monoclinic transformation and that although the overall residual stress in the bands is compressive, the tensile stress in the tetragonal zirconia phase is enhanced. The experimental data are compared with the predictions of a stochastic theory for three‐phase materials and with models for the stress distribution within a deformation band. The region ahead of the deformation band is subject to an additional, superimposed tensile stress whose magnitude compares favorably with the predictions of a superdislocation model presented.
Viscous Sintering of Spherical Particles via Finite Element Analysis
Authors: Martínez‐Herrera Jorge I. , Derby Jeffrey J.
Published: September 2005

A robust finite element model is employed to study the viscous sintering of three‐dimensional, axisymmetric particles from several initial configurations. Particle shape evolution and flow fields are presented which yield new insight into the behavior of these systems. The effects of the initial particle size distribution and configuration are considered.Model predictions are validated by direct comparisons with experimental measurements.
Chemical Stability of the Fiber Coating Matrix Interface in Silicon‐Based Ceramic Matrix Composites
Authors: Lee Kang N. , Jacobson Nathan S.
Published: September 2005

Carbon and boron nitride are used as fiber coatings in silicon‐based composites. In order to assess the long‐term stability of these materials, reactions of carbon/Si3N4 and BN/SiC were studied at high temperatures with Knudsen effusion, coupon tests, and by microstructural examination. In the carbon/Si3N4 system, carbon reacted with Si3N4 to form gaseous N2 and SiC. The formation of SiC limited further reaction by physically separating the carbon and Si3N4. Consequently, the development of high p(N2) at the interface, predicted from thermochemical calculations, did not occur, thus limiting the potential deleterious effects of the reaction on the composite. Strong indications of a reaction between BN and SiC were shown by TEM and SIMS analysis of the BN/SiC interface. In long‐term exposures, this reaction can lead to a depletion of a BN coating and/or an unfavorable change of the interfacial properties, limiting the beneficial effects of the coating.
Surface Precipitation Route for the Development of Cordierite‐Zirconia Composites
Authors: Jang Hyun M.
Published: September 2005

Based on the interfacial electrochemical properties of aqueous cordierite dispersion, a novel interfacial scheme for fabricating cordierite‐ZrO2 composite with a dense and homogeneous microstructure was proposed and tested. In the present processing route, cordierite particles were first uniformly coated with a thin layer (∼40 nm) of aluminum hydroxide by an in situ surface‐induced coating. Then, a controlled surface precipitation of ultrafine zirconium hydroxide precursor onto the coated cordierite particles was performed to obtain a composite with a uniform spatial distribution of the dispersed ZrO2 particles throughout the matrix. The coated layer acted to suppress the formation of zircon phase during sintering. The enhanced fracture toughness observed in the presence of ZrO2 was partly attributed to the t→m transformation toughening of the dispersed tetragonal ZrO2 particles.
Thermal Conductivity of Polycrystalline Materials
Authors: Kumar Susmit , Singh Raj N.
Published: September 2005

A three‐dimensional Poisson‐Voronoi tessellation model is used to simulate the microstructure of polycrystalline materials consisting of random shape and size grains. The model is used to calculate the thermal conductivity of homogeneous and isotropic polycrystalline materials which may be anisotropic on a microlevel. The calculated thermal conductivity is found to be close to the experimental and the theoretical values. For trigonal, tetragonal, and hexagonal materials, the effective thermal conductivity shows a systematic variation with the change in the anisotropy of the single crystal.
Formation of MgO‐B4C Composite via aThermite‐Based Combustion Reaction
Authors: Wang Lily L. , Munir Zuhair A. , Holt J. Birch
Published: September 2005

The combustion synthesis of MgO‐B4C composites was investigated by coupling a highly exothermic Mg‐B2O3 thermite reaction with a weakly exothermic B4C formation reaction. Unlike the case of using Al as the reducing agent, the interaction between Mg and B2O3 depends on the surrounding inert gas pressure due to the high vapor pressure of Mg. The interaction changes from one involving predominantly gaseous Mg and liquid B2O3 to one involving liquid Mg and liquid B2O3 as the pressure increases. At low inert gas pressure, the initiation temperature is found to be just below the melting point of Mg (650°C). As the inert gas pressure increases, the vaporization loss of reactants is reduced, and this in turn increases the combustion temperature, which promotes greater grain growth of the product phases, MgO and B4C. The particle size of B4C increased from about 0.2 to 5 μm as the pressure changed from 1 to 30 atm.
Computer Simulation of Twin Formation during the Displacive c→t′ Phase Transformation in the Zirconia‐Yttria System
Authors: Fan Danan , Chen Long‐Qing
Published: September 2005

The kinetics of the displacive cubic‐to‐tetragonal (c→t′) phase transformation and the evolution of twin structure of Y2O3‐ZrO2 systems were investigated by employing the time‐dependent Ginzburg‐Landau equations, in which the displacive modes were described by nonconserved order parameters. The original elasticity theory of Khachaturyan, in a sharp‐interface description for an arbitrary distribution of second‐phase precipitates in a matrix, was reformulated in the spirit of the diffuse interface theory of Cahn and Hilliard for interphase boundaries. The influence of thermodynamic conditions, clamped or stress‐free, on microstructure evolution was studied. Our computer simulation showed that, even though the thermodynamic equilibrium is the single domain under a stress‐free condition, the twin structure can form during a kinetic path of the phase transformation, and it is the clamped condition which results in the formation of stable twins.
Effect of Stacking Faults on the X‐ray Diffraction Profiles of β‐SiC Powders
Authors: Pujar Vijay V. , Cawley James D.
Published: September 2005

X‐ray diffraction patterns of β‐SiC (3C or the cubic polytype of SiC) powders often exhibit an additional peak at d= 0.266 nm, high background intensity around the (111) peak, and relative intensities for peaks which differ from those predicted from the crystal structure. Computer simulations were used to show that all these features are due to stacking faults in the powders and not due to the presence of other polytypes in the powders. Such simulations allow diffraction patterns to be generated for different types, frequencies, and spatial distribution of faults. Comparison of thesimulation results to the XRD data indicates that the β‐SiC particles consist either of heavily faulted clusters distributed irregularly between regions that have only occasional faults or twins, or the powders consist of two types of particles with different populations of faults: those with a high density of faults and those with only twins or occasional faults. Additional information is necessary to determine which description is correct. However, the simulation results can be used to rule out certain fault configurations.
Elastic Response and Effect of Transverse Cracking in Woven Fabric Brittle Matrix Composites
Authors: Kuo Wen‐Shyong , Chou Tsu‐Wei
Published: September 2005

This paper examines the linear elastic tensile and fracture behavior of biaxial plain weave SiC/SiC ceramic woven fabric composites. Iso‐phase mode and random‐phase mode have been adopted to simulate multilayer stacking and to predict the initial linear elastic constants. It has been found that both modes predict very close results. Porosities in the composite affect the stiffness significantly, while fiber undulation shows only minimal effect. The nonlinear stress‐strain relation of the composite is due to transverse cracks, which initiate mainly from interyarn pores. In the second part of this paper, two methods, classical fracture mechanics and energy balance approach, have been used to examine the crack initiation and growth. A finite element method and a modified shear‐lag method have been developed to evaluate the stress distribution in the yarn with transverse cracks. The composite stiffness reduction due to transverse cracking has been obtained by both the finite element and shear‐lag methods. Strain energy release rates of the growth of transverse cracks have been studied by the crack‐closure procedure, using finite element methods. Effects of the yarn size and crack position on the strain energy release rate have been quantified. It is concluded that thinner yarns lead to higher critical strains for transverse cracking.
Role of Donor and Acceptor Ions in the Dielectric Loss Tangent of (Zr0.8Sn0.2)TiO4 Dielectric Resonator Material
Authors: Michiura Nobuhiko , Tatekawa Tsutomu , Higuchi Yukio , Tamura Hiroshi
Published: September 2005

The role of donor and acceptor ions in the dielectric loss tangent of (Zr,Sn)TiO4 was investigated at frequencies from 0.1 kHz to 9 GHz. When a specimen was doped with Fe2O3, the loss tangent increased drastically at microwave frequencies. This increase is explained by a large concentration of Fe3+ ions and oxygen vacancies in the grains. When the specimen was doped with Ta2O5 and then annealed in a reducing atmosphere, electrical resistivity decreased and tan δ increased extremely at low frequencies but trivially at microwave frequencies. The high microwave Q value of Tadoped specimens is explained by assuming the Ta ions in the crystal to be tetravalent. Dielectric loss is determined predominantly by space charge polarization at low frequencies and by the disordered charge distribution at microwave frequencies.
Some Properties of Aluminum Carbide Powder Prepared by the Pyrolysis of Alkylaluminu
Authors: Itatani Kiyoshi , Hasegawa Minoru , Aizawa Mamoru , Howell F. Scott , Kishioka Akira , Kinoshita Makio
Published: September 2005

Ultrafine aluminum carbide (Al4C3) powders with crystallite sizes of <40 nm were prepared by the pyrolyses of alkylaluminums, i.e., trimethylaluminum (Al(CH3)3: TMAL), triethylaluminum (Al(C2H5)3: TEAL), triisobutylaluminum (Al(i‐C4H9)3: TIBAL) at a temperature between 950° and 1100°C. Although the pyrolysis of TMAL produced Al4C3 at 950°C, the pyrolysis temperature of TEAL to produce Al4C3 was raised up to 1100°C. The pyrolysis of TIBAL at 1100°C produced not only crystalline Al4C3 but also amorphous oxycarbide. The TEAL‐derived powder had the highest true density (2.89 g.cm−3 or 97% of the theoretical density) among the three kinds of powders.
Constrained‐Film Sintering of a Borosilicate Glass: In Situ Measurement of Film Stresses
Authors: Bang Jaecheol , Lu Guo‐Quan
Published: September 2005

We have measured in‐plane stresses developed in a borosilicate glass (BSG) film during its constrained sintering on a rigid substrate. Samples were prepared by casting BSG slurries on a silicon substrate and sintered inside a hot stage at 715°C just above the glass‐softening temperature. Inplane stresses from the constrained‐film sintering were determined by wafer‐curvature measurements using an optical system. The measured stresses were tensile and rose rapidly from zero to a maximum level of 20 kPa during the initial stage of sintering and gradually decreased to zero at the final stage; these stresses were considerably smaller than those calculated from available microstructural models. We also measured the densification profiles of the free and constrained films. The stresses had no apparent effect on the densification profile of the constrained film up to 90% relative density; but beyond that, the densification kinetics were reduced in the constrained film. We believe that the stresses could have prevented a few large pores from shrinking during the initial stage of sintering, which then leads to an overall lower density and larger pores in the constrained film.
Diffraction Method Detection of Local Lattice Distortion in AIN Ceramics by Convergent Beam Electron
Authors: Nakahata Seiji , Sogabe Kouichi , Matsuura Takahiro , Yamakawa Akira
Published: September 2005

Lattice distortions in polycrystalline aluminum nitride (A1N) were observed by convergent beam electron diffraction (CBED). CBED patterns show that the A1N crystal lattice is distorted near the grain‐boundary phase. This is a result of sintering aids, possibly due to the difference in the thermal expansion between the AlN crystal and the grain‐boundary phase.
Preservation of platelet responsiveness to nitroglycerine despite development of vascular nitrate tolerance
Authors: Holmes Andrew S. , Chirkov Yuliy Y. , Willoughby Scott R. , Poropat Susan , Pereira Jeremy , Horowitz John D.
Published: September 2005

Aims

Organic nitrates, via nitric oxide (NO) release, induce vasodilatation and inhibit platelet aggregation. Development of nitrate tolerance in some vascular preparations may be associated with diminished responsiveness to NO. To date it is not known to what extent vascular tolerance to organic nitrates is associated with acquired platelet hypo‐responsiveness to NO. In the current study we compared the acute and chronic effects of sustained release (SR) isosorbide 5′ mono‐nitrate (ISMN) and transdermal nitroglycerine (TD‐NTG) on blood vessels (effects on apparent arterial stiffness) and platelets (effects on responsiveness to NO donors) in patients with stable angina pectoris (SAP).

Methods

Patients (n = 34) with SAP entered a blinded randomized crossover study of ISMN (120 mg) vs. intermittent TD‐NTG (15 mg 24 h−1). Effects of each nitrate on pulse wave reflection (augmentation index (AIx)), platelet response to adenosine di‐phosphate (ADP 1 µmol l−1), nitroglycerine (NTG 100 µmol l−1) and the non‐nitrate NO donor sodium nitroprusside (SNP 10 µmol l−1), were measured pre‐dose, 4 and 8 h post dose, on three occasions: 1) at the end of a pre‐nitrate phase, 2) after dosing for 7 days and 3) following 14 days of full dose therapy with either nitrate.

Results

Acutely, both ISMN and TD‐NTG markedly reduced AIx. After 14 days, these effects were significantly attenuated (anova, P = 0.018) but not abolished, indicating development of nitrate tolerance. Neither nitrate preparation affected ADP (1 µmol l−1)‐induced platelet aggregation. Platelet responsiveness to NTG (100 µmol l−1) and SNP (10 µmol l−1) was not diminished during chronic nitrate therapy, and there was no evidence of ‘rebound’ hyper‐aggregability during ‘nitrate‐free’ periods.

Conclusions

Chronic therapy with either ISMN or TD‐NTG is associated with development of vascular tolerance. Despite the induction of vascular tolerance, platelet responsiveness to NTG and SNP remains unaffected. Therefore, development of vascular tolerance is unlikely to compromise the anti‐aggregatory effects of organic nitrates, or those of endogenous NO.
The quality of information on monitoring for haematological adverse drug reactions
Authors: Ferner R. E. , Coleman Jamie , Pirmohamed Munir , Constable Simon A. , Rouse Andrew
Published: September 2005

Aims To examine the adequacy of instructions to monitor for haematological adverse drug reactions in the Summary of Product Characteristics.

Methods We searched the United Kingdom eMedicines Compendium to identify instructions to monitor for haematological adverse drug reactions, and selected 84 Summaries of Product Characteristics for nonhaematological drugs, which were then scored independently by five clinicians, using a scale we devised, the Systematic Instructions for Monitoring (SIM) score. A subset of comparable summaries from Australian and United States summaries was also examined.

Results The SIM scores for the five clinicians agreed well: Kendall's coefficient of concordance = 0.937, P < 0.0001. The median SIM score for the 84 UK summaries was 13 [95% confidence interval (CI) for median 12, 15] out of a possible 31. Over 40% fell below a hypothetical minimally acceptable score of 12/31. SIM scores were on average 2.0 (95% CI 0.4, 3.8) higher for Australian summaries; US summaries had intermediate scores that did not significantly differ from those in Australia or the UK.

Conclusions Instructions on monitoring for adverse drug reactions are often inadequate. Pharmaceutical companies and regulatory agencies should produce clear guidance on monitoring, and the data to support it.
Effects of food and formulation on the relative bioavailability of bismuth biskalcitrate, metronidazole, and tetracycline given for Helicobacter pylori eradication
Authors: Spénard Jean , Aumais Christian , Massicotte Julie , Brunet Jean‐Sébastien , Tremblay Claude , Grace Michael , Lefebvre Marc
Published: September 2005

Aims

To evaluate the effects of food and formulation on the pharmacokinetics of bismuth biskalcitrate, metronidazole and tetracycline when combined in a new 3‐in‐1 single capsule (BMT) for eradication of Helicobacter pylori.

Methods

In a randomized, 3 × 3 cross‐over design, 23 healthy males received one dose of BMT in the fed and fasting states and equivalent doses of the three drugs given together but as separate capsules while fasting. Bioequivalence was evaluated according to 90% confidence intervals (CIs) of ratios of geometric least square means for Cmax, AUCt, and AUC∞.

Results

With respect to food, none of the three drugs met bioequivalence guidelines. Bismuth had lower limit CIs ranging from 12% for Cmax to 25% for AUC∞. The corresponding values for tetracycline were 59% and 51%. Metronidazole had a lower limit CI of 74% for Cmax. With respect to formulation, bismuth had lower limits of CIs ranging from 39% for Cmax to 50% for AUCt and higher limits of 146% for AUCt, metronidazole met bioequivalence guidelines, and tetracycline had lower limits of CIs between 72% for AUCt and 74% for AUC∞.

Conclusions

Food significantly decreased the relative bioavailability of each drug but formulation was without effect. This decrease may be beneficial when a local gastric action is needed, as confirmed by a near 90% eradication rate when this combined capsule is administered with food to treat gastro‐duodenal local infection by H. pylori.
S‐Naproxen and desmethylnaproxen glucuronidation by human liver microsomes and recombinant human UDP‐glucuronosyltransferases (UGT): role of UGT2B7 in the elimination of naproxen
Authors: Bowalgaha Kushari , Elliot David J. , Mackenzie Peter I. , Knights Kathleen M. , Swedmark Stellan , Miners John O.
Published: September 2005

Aims

To characterize the kinetics of S‐naproxen (‘naproxen’) acyl glucuronidation and desmethylnaproxen acyl and phenolic glucuronidation by human liver microsomes and identify the human UGT isoform(s) catalysing these reactions.

Methods

Naproxen and desmethylnaproxen glucuronidation were investigated using microsomes from six and five livers, respectively. Human recombinant UGTs were screened for activity towards naproxen and desmethylnaproxen. Where significant activity was observed, kinetic parameters were determined. Naproxen and desmethylnaproxen glucuronides were measured by separate high‐performance liquid chromatography methods.

Results

Naproxen acyl glucuronidation by human liver microsomes followed biphasic kinetics. Mean apparent Km values (±SD, with 95% confidence interval in parentheses) for the high‐ and low‐affinity components were 29 ± 13 µm (16, 43) and 473 ± 108 µm (359, 587), respectively. UGT 1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10 and 2B7 glucuronidated naproxen. UGT2B7 exhibited an apparent Km (72 µm) of the same order as the high‐affinity human liver microsomal activity, which was inhibited by the UGT2B7 selective ‘probe’ fluconazole. Although data for desmethylnaproxen phenolic glucuronidation by human liver microsomes were generally adequately fitted to either the single‐ or two‐enzyme Michaelis–Menten equation, model fitting was inconclusive for desmethylnaproxen acyl glucuronidation. UGT 1A1, 1A7, 1A9 and 1A10 catalysed both the phenolic and acyl glucuronidation of desmethylnaproxen, while UGT 1A3, 1A6 and 2B7 formed only the acyl glucuronide. Atypical glucuronidation kinetics were variably observed for naproxen and desmethylnaproxen glucuronidation by the recombinant UGTs.

Conclusion

UGT2B7 is responsible for human hepatic naproxen acyl glucuronidation, which is the primary elimination pathway for this drug.
No positive association between adrenergic receptor variants of α2cDel322–325, β1Ser49, β1Arg389 and the risk for heart failure in the Japanese population
Authors: Nonen Shinpei , Okamoto Hiroshi , Akino Masatoshi , Matsui Yutaka , Fujio Yasushi , Yoshiyama Minoru , Takemoto Yasuhiko , Yoshikawa Junichi , Azuma Junichi , Kitabatake Akira
Published: September 2005

Aims

We investigated the correlation of adrenergic receptor polymorphisms, α2cDel322–325, β1Ser49Gly and β1Arg389Gly, with the risk of heart failure in the Japanese population.

Methods

These polymorphisms were analysed by polymerase chain reaction‐restriction fragment length polymorphism in patients with chronic heart failure due to idiopathic dilated cardiomyopathy (DCM) and compared with the control group.

Results

There were no differences or any trends in the allele and genotype frequencies of the β1Ser49Gly and β1Arg389Gly polymorphisms. The allele frequency of the α2cDel322–325 variant was lower in patients than in controls (0.11 vs. 0.04, P = 0.011 < 0.017, by Bonferroni correction), while the genotype frequency just failed to reach significance (P = 0.022 > 0.017, by Bonferroni correction).

Conclusions

In this population, the variants β1Ser49, β1Arg389, and α2cDel322–325 do not appear to be risk factors for chronic heart failure due to DCM. The α2cDel322–325 variant may in fact confer some protection.
Rhythm vs. rate control of atrial fibrillation meta‐analysed by number needed to treat
Authors: Kumana Cyrus R. , Cheung Bernard M. Y. , Cheung Giselle T. Y. , Ovedal Tori , Pederson Bjorn , Lauder Ian J.
Published: September 2005

Background

Whenever feasible, rhythm control of atrial fibrillation (AF) was generally preferred over rate control, in the belief that it offered better symptomatic relief and quality of life, and eliminated the need for anticoagulation. However, recent trials appear to challenge these assumptions.

Aims

To explore the desirability of rhythm vs. rate control of AF by systematic review of pertinent, published, randomized controlled trials (RCTs) and a meta‐analysis by number needed to treat (NNT) year−1, with respect to diverse clinically important outcomes.

Methods

RCTs of outcome primarily comparing rate vs. rhythm control in patients with spontaneous AF were identified. For each outcome and assuming rhythm control to be the active treatment, relative risk reduction (RRR) and NNT year−1 were derived for individual trials together with an NNT year−1 for all trials combined; corresponding 95% confidence intervals (CI) were also calculated. Adverse drug reaction (ADR) and quality of life reporting were also assessed.

Results

In all, data from five suitable RCTs (entailing 5239 patients) were analysed. For hospitalization, available RRRs and NNT year−1 values were all clinically and statistically significant. Overall, one additional patient was hospitalized for every 35 assigned to rhythm control (95% CI 27, 48). For the endpoints of death, ‘ischaemic’ stroke and ‘non‐CNS’ bleeding, there was no significant difference. ADRs were significantly more common in rhythm control patients, whereas quality of life assessments revealed no difference. Thromboembolism was associated with cessation of or subtherapeutic anticoagulation, irrespective of treatment assignment.

Conclusion

Reduced risk of hospitalization and non‐inferiority for other endpoints all favour rate control, the less costly strategy. If symptoms of AF are not a problem, treatment should target optimizing rate control and more widespread and effective prophylactic anticoagulation.
Population pharmacokinetics of lopinavir in combination with ritonavir in HIV‐1‐infected patients
Authors: Crommentuyn K. M. L. , Kappelhoff B. S. , Mulder J. W. , Mairuhu A. T. A. , Van Gorp E. C. M. , Meenhorst P. L. , Huitema A. D. R. , Beijnen J. H.
Published: September 2005

Aims

To develop a population pharmacokinetic model for lopinavir in combination with ritonavir, in which the interaction between both drugs was characterized, and in which relationships between patient characteristics and pharmacokinetics were identified.

Methods

The pharmacokinetics of lopinavir in combination with ritonavir were described using NONMEM (version V, level 1.1). First, ritonavir data were fitted to a previously developed model to obtain individual Bayesian estimates of pharmacokinetic parameters. Hereafter, an integrated model for the description of the pharmacokinetics of lopinavir with ritonavir was designed.

Results

From 122 outpatients 748 lopinavir and 748 ritonavir plasma concentrations were available for analysis. The interaction between the drugs was described by a time‐independent inverse relationship between the exposure to ritonavir over a dosing‐interval and the apparent clearance (CL/F) of lopinavir. The model parameters volume of distribution and absorption rate constant were 61.6 l (95% prediction interval (PI) 22.4, 83.7) and 0.564 h−1 (95% PI 0.208, 0.947), respectively. The model yielded a theoretical value for the CL/F of lopinavir without ritonavir of 14.8 l h−1 (95%PI 12.1, 20.1), which translates to a value of 5.73 l h−1 in the presence of ritonavir. The only factor with significant effect on the pharmacokinetics was concurrent use of non‐nucleoside reverse transcriptase inhibitors (NNRTI), which increased the CL/F of lopinavir by 39% (P < 0.001).

Conclusions

We have developed a model that has defined a time‐independent inverse relationship between the exposure to ritonavir and the CL/F of lopinavir, and provided an adequate description of the pharmacokinetic parameters for the latter. Concomitant use of the NNRTIs efavirenz and nevirapine increased the CL/F of lopinavir.
Within‐ and between‐ subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects
Authors: Hanna Julia , Foster David J.R. , Salter Amy , Somogyi Andrew A. , White Jason M. , Bochner Felix
Published: September 2005

Aims

To investigate within‐ and between‐subject variability of the pharmacodynamics and pharmacokinetics of (R)‐ and (S)‐methadone in methadone maintenance subjects at steady‐state.

Methods

Six non‐holder subjects were studied on three occasions at 7–16 day intervals; doses (20–170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10–12 times over a 24‐h inter‐dosing interval. All pharmacodynamic data were expressed as the area under the end‐point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between‐ to within‐subject variation, with corresponding 95% confidence intervals (CI) for within‐subject variation at the average value.

Results

Subjects were relatively consistent between occasions, whereas there was much greater between‐subject variability (P < 0.02) for all measures. Estimates of the ratio of between‐ to within‐subject variation ranged from 2.2–12.8 for pharmacodynamic measures, and 1.3–7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within‐subject measures ranged ≤ 2‐fold, while this was greater for subjective direct opioid effects (4.2‐fold). For CL/F of the active (R)‐methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within‐subject measures ranging ≤ 2‐fold. (S)‐methadone CL/F demonstrated greater within‐subject variability (3.4‐fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between‐ to within‐subject variance.

Conclusions

Non‐holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1–2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population.
Long‐term incubation with IL‐4 and IL‐10 oppositely modifies procoagulant activity of monocytes and modulates the surface expression of tissue factor and tissue factor pathway inhibitor
Authors: Paysant Jérôme , Soria Claudine , Cornillet‐Lefèbvre Pascale , Nguyen Philippe , Lenormand Bernard , Mishal Zohar , Vannier Jean‐Pierre , Vasse Marc
Published: September 2005

Monocytes can be induced to express both tissue factor (TF) and its inhibitor, TF pathway inhibitor‐1 (TFPI‐1). A short incubation (<6 h) with interleukin (IL)‐4 and IL‐10, two potent deactivators of monocyte functions, has been shown to modulate the synthesis and expression of TF by monocytes activated by lipopolysaccharide, but the consequences of longer incubations (up to 96 h) on both TF and TFPI‐1 are unknown. The results of this study showed that adherent monocytes in culture spontaneously expressed TF and TFPI and that prolonged incubation with IL‐10 induced a time‐ and dose‐dependent decrease of monocyte TF synthesis, and an accumulation of TF/TFPI‐1 complexes at the moncyte surface, suggesting a decreased clearance of these complexes. In contrast, IL‐4 induced a time‐ and dose‐dependent increase in TF synthesis, which remained intracytoplasmic, as shown by confocal microscopy. Surprisingly, TF:antigen (Ag) was decreased at the monocyte surface, but the procoagulant activity (PCA) of IL‐4‐treated monocytes was increased, as a result of more pronounced decrease of TFPI‐1:Ag expression than that of TF. In conclusion, prolonged incubation with IL‐4 and IL‐10 oppositely modified PCA of cultured monocytes, and altered TF and TFPI trafficking and clearance. These data explain the respective deleterious or benefit effects of IL‐4 or IL‐10 in atherothrombosis.
Chronic fatigue syndrome is associated with diminished intracellular perforin
Authors: Maher K J , Klimas N G , Fletcher M A
Published: September 2005

Chronic fatigue syndrome (CFS) is an illness characterized by unexplained and prolonged fatigue that is often accompanied by abnormalities of immune, endocrine and cognitive functions. Diminished natural killer cell cytotoxicity (NKCC) is a frequently reported finding. However, the molecular basis of this defect of in vitro cytotoxicy has not been described. Perforin is a protein found within intracellular granules of NK and cytotoxic T cells and is a key factor in the lytic processes mediated by these cells. Quantitative fluorescence flow cytometry was used to the intracellular perforin content in CFS subjects and healthy controls. A significant reduction in the NK cell associated perforin levels in samples from CFS patients, compared to healthy controls, was observed. There was also an indication of a reduced perforin level within the cytotoxic T cells of CFS subjects, providing the first evidence, to our knowledge, to suggest a T cell associated cytotoxic deficit in CFS. Because perforin is important in immune surveillance and homeostasis of the immune system, its deficiency may prove to be an important factor in the pathogenesis of CFS and its analysis may prove useful as a biomarker in the study of CFS.
Identification of paramyosin T cell epitopes associated with human resistance toSchistosoma mansonireinfection
Authors: Fonseca C T , Cunha-Neto E , Goldberg A C , Kalil J , De Jesus A R , Carvalho E M , Correa-Oliveira R , Hammer J , Sidney J , Sette A , Oliveira S C
Published: September 2005

Paramyosin, a Schistosoma mansoni myoprotein associated with human resistance to infection and reinfection, is a candidate antigen to compose a subunit vaccine against schistosomiasis. In this study, 11 paramyosin peptides selected by TEPITOPE algorithm as promiscuous epitopes were produced synthetically and tested in proliferation and in vitro human leucocyte antigen (HLA)-DR binding assays. A differential proliferative response was observed in individuals resistant to reinfection compared to individuals susceptible to reinfection in response to Para (210–226) peptide stimulation. In addition, this peptide was able to bind to all HLA-DR molecules tested in HLA-DR binding assays, confirming its promiscuity. Para (6–22) and Para (355–371) were also shown to be promiscuous peptides, because they were able to bind to the six and eight most prevalent HLA-DR alleles used in HLA-DR binding assays, respectively, and were also recognized by T cells of the individuals studied. These results suggest that these paramyosin peptides are promising antigens to compose an anti-schistosomiasis vaccine.
Increased plasma N‐terminal pro‐B‐type natriuretic peptide and markers of inflammation related to atherosclerosis in patients with primary hyperparathyroidism
Authors: Øgard Christina Gerlach , Engelmann Mads D. , Kistorp Caroline , Nielsen Steen Levin , Vestergaard Henrik
Published: September 2005

Objective  Increased risk of cardiovascular disease has been reported in patients with primary hyperparathyroidism (PHPT). The aim of this study was to evaluate novel plasma risk markers of cardiovascular disease in patients with PHPT.

Design  PHPT patients were evaluated with a control group. Patients who underwent parathyroidectomy were re‐evaluated after 7 and 18 months.

Patients  Forty‐five PHPT patients and 40 matched controls participated. Seventeen patients underwent parathyroidectomy.

Measurements  Plasma N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), high‐sensitivity C‐reactive protein (CRP), interleukin‐6 (IL‐6) and tumour necrosis factor alpha (TNF‐α), lipids and blood pressure were measured. In 27 patients a bicycle exercise test and radionuclide angiography were performed, and repeated in those who underwent parathyroidectomy.

Results  Plasma NT‐proBNP, CRP and TNF‐α, but not IL‐6, were higher in patients with PHPT than in controls (P < 0·01 and P = 0·17, respectively). In patients with PHPT, NT‐proBNP correlated with systolic blood pressure, left ventricular end‐diastolic volume, and peak oxygen uptake (all P < 0·01). Log CRP correlated with systolic and diastolic blood pressure (both P < 0·05) and log IL‐6 (P < 0·01). No significant correlations were observed between PTH or calcium and risk markers of cardiovascular disease. No decrease in NT‐proBNP, markers of inflammation or blood pressure was observed after parathyroidectomy.

Conclusions  Our data suggest that hypertension or other factors, rather than plasma calcium or PTH, could explain the increased levels of the inflammatory markers and NT‐proBNP in PHPT. We therefore suggest that aggressive treatment of hypertension should be initiated in patients with PHPT to try to reduce the increased cardiovascular mortality described in PHPT. Further prospective studies are needed to validate the suggestion that increased levels of NT‐proBNP and inflammatory markers also represent strong prognostic markers of cardiovascular disease in patients with PHPT.
Alterations in the oxidant‐antioxidant status in prepubertal children with growth hormone deficiency: effect of growth hormone replacement therapy
Authors: Mohn Angelika , Di Marzio Daniele , Giannini Cosimo , Capanna Rita , Marcovecchio Maria , Chiarelli Francesco
Published: September 2005

Objective  Growth hormone deficiency (GHD) in adults is associated with increased oxidative stress determined by the underlying GH–IGF‐1 axis alterations. Despite GHD being a common diagnosis in children with short stature, no data on the oxidant/antioxidant status are available in this age group. This study was designed to detect differences in oxidative stress parameters between prepubertal GH‐deficient children and healthy controls. Furthermore, the effect of 12 months of conventional GH replacement (rGH) on oxidant–antioxidant status was evaluated in the GHD group only.

Patients  Ten (nine males and one female) prepubertal children (mean age 9·1 ± 1·3 years) with GHD were recruited and matched for sex and age (9·2 ± 1·9 years) with 20 healthy controls (18 males and two females).

Measurements  At study entry, lag phase, an index of susceptibility of low density lipoprotein (LDL) to in vitro oxidation, malondialdehyde (MDA) and vitamin E were measured in all subjects. These parameters were also evaluated in GH‐deficient children after 12 months of rGH treatment.

Results  The lag phase was significantly decreased in GH‐deficient children compared to healthy controls (15·50 ± 7·4 vs. 43·00 ± 9·2 min; P = 0·0007), while MDA was significantly increased (1·33 ± 0·38 vs. 0·46 ± 0·10 nmol/mg; P = 0·0006). Vitamin E levels were significantly decreased (22·44 ± 9·57 vs. 35·38 ± 16·49 µmol/l; P = 0·001). IGF‐1 and IGFBP‐3 correlated directly to lag phase (r = 0·48; P = 0·01; r = 0·63, P = 0·002, respectively) and to vitamin E (r = 0·59, P = 0·003; r = 0·58, P = 0·006, respectively). By contrast, IGF‐1 and IGFBP‐3 correlated indirectly to MDA (r = –0·47, P = 0·01; r =−0·65, P = 0·002, respectively). After 1 year of rGH therapy, lag phase (39·32 ± 15·24 min; P = 0·005) and vitamin E (34·9 ± 7·7 µmol/l; P = 0·005) increased significantly, while MDA decreased significantly (0·71 ± 0·42 nmol/mg; P = 0·005), reaching normal levels.

Conclusions  These data show that children with GHD have substantially increased oxidative stress parameters compared to healthy controls and demonstrate a normalization of these parameters after 1 year of rGH therapy.