Pharmacokinetics of single intravenous and oral doses of dolasetron mesylate in healthy elderly volunteers

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5-HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half-life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vd beta) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the (+)-enantiomer of the reduced metabolite, which accounted for 25.35% (+/- 7.79%) and 18.88% (+/- 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high-dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.     

Rescue of a maize mitochondrial cytochrome oxidase mutant by tissue culture

The maize NCS6 mitochondrial mutation is a partial deletion of the cytochrome oxidase subunit 2 gene (cox2) that survives heteroplasmically in the plant. Mutant mitochondria segregate from normal mitochondria during somatic development giving rise to defective sectors on the plants, including areas of kernel abortion on the ears. Embryos from NCS6 kernels can be rescued by tissue culture. Slowly growing Type II callus derived from one of these embryos has been shown by PCR analysis to be homoplasmic for the mutation, carrying only the defective mitochondrial cox2 gene. Most of the rescued embryos were heteroplasmic for normal and mutant genes and heteroplasmy was maintained in the callus cultures. However, when suspension cultures were initiated from heteroplasmic calli, normal cells were shown to have a selective advantage. When the homoplasmic cox2 mutant callus cultures were placed on regeneration medium, plantlets did not regenerate. Heteroplasmic calli were capable of regeneration under the same conditions. These studies suggest that the functioning of mitochondrial cytochrome oxidase is not essential for growth as callus, but is required for the differentiation and development of plants.     

Synthesis of a novel small diameter polyurethane vascular graft with reactive binding sites

Development of a small diameter (4 mm inner diameter [ID]) prosthetic vascular graft with functional groups accessible for covalent binding of recombinant hirudin (a potent anticoagulant) should create a more hemocompatible surface. The purpose of this study was to develop a technique for generating carboxylic acid groups on the surface of precast 4 mm ID poly-(carbonate urea)-urethane vascular grafts and to evaluate the accessibility of these groups. A polycarbonate based urethane with the chain extender 2,2-bis(hydroxymethyl)propionic acid was synthesized. A precast 4 mm ID poly(carbonate urea)-urethane vascular graft (Chronoflex [CF]; CardioTech International, Woburn, MA) was then placed into a 4% carboxylated polyurethane (cPU) solution (in 1% dimethyl acetamide) and incubated for 30 minutes (cPU graft). To determine the accessibility of the carboxylic acid groups, a standard textile technique using methylene blue dye was used. Macroscopic cross-sections, which were cut and evaluated for dye penetration, showed greatest concentration of carboxylic acid groups at the luminal and capsule surfaces, with minimal penetration into the mid-portion of the graft. Analysis of dye baths for absorbance reduction resulted in the cPU grafts having 3.7-fold and 5.4-fold more accessible carboxylic acid groups compared with untreated and dimethyl acetamide dipped CF grafts. Thus, a novel small diameter vascular graft has been developed that contains reactive carboxylic acid groups accessible for protein binding.     

Pt based nanocomposites (mono/bi/tri-metallic) decorated using different carbon supports for methanol electro-oxidation in acidic and basic media

Pt based mono/bi/tri-metallic nanocomposites on different carbon based supports (activated carbon (AC), carbon nanotubes (CNTs) and carbon nanofibers (CNFs)) were synthesised and Pt surface enrichment achieved. The overall theoretical metallic content (Pt + Au + Sn) was 20% (w/w) in all mono/bi/tri-metallic nanocomposites and was found to be uniformly distributed in the supporting matrix (80%). The surface morphology and composition of the synthesised materials was characterised using scanning electron microscopy (SEM), energy-dispersive X-ray spectrometry (EDX), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), thermo-gravimetric analysis (TGA), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), while cyclic voltammetry was employed in order to confirm their typical metallic electrochemical characteristics. Electrochemical measurements indicated that Pt(2)Au(1)Sn(1) trimetallic catalysts demonstrated a significantly higher electrochemically active surface area relative to activated carbon supported PtAu based bimetallic counterparts. The results show that the CNT based trimetallic catalyst (Pt(2)Au(1)Sn(1)/CNT) showed greatest electroactive surface area (49.3 m(2)/g) and current density for methanol oxidation in acidic (490 mA mg(-1) Pt) as well as basic (1700 mA mg(-1) Pt) conditions. Results demonstrated that in comparison to Au/C and Sn/C (no/negligible response), the presence of a small amount of Pt in the Au and Sn based nanocomposites, significantly modified the catalytic properties. The activated carbon supported bimetallic (Pt(1)Au(3)/C) catalyst showed reasonably good response (260 mA mg(-1) Pt) among all bimetallic nanomaterials examined. The current response achieved for Pt(2)Au(1)Sn(1)/CNT was 1.9 times (in acidic media) and 2.1 times (in basic media) that for synthesised Pt/C in terms of per mg Pt activity. Overall the methanol oxidation studies demonstrated that the presence of Au and Sn in Pt based catalysts strongly indicated their capacity to reduce the precious Pt content required for this application, demonstrating the role of Au in improving current/potential response and signifying the importance of supporting matrices.     

A Lattice Model for Viscoelastic Fracture

A plane, periodic, square-cell lattice is considered,consisting of point particles connected by mass-less viscoelastic bonds.Homogeneous and inhomogeneous problems for steady-state semi-infinitecrack propagation in an unbounded lattice and lattice strip are studied.Expressions for the local-to-global energy-release-rate ratios, stressesand strains of the breaking bonds as well as the crack openingdisplacement are derived. Comparative results are obtained forhomogeneous viscoelastic materials, elastic lattices and homogeneouselastic materials. The influences of viscosity, the discrete structure,cell size, strip width and crack speed on the wave/viscous resistancesto crack propagation are revealed. Some asymptotic results related to animportant asymptotic case of large viscosity (on a scale relative to thelattice cell) are shown. Along with dynamic crack propagation, a theoryfor a slow crack in a viscoelastic lattice is derived.     

A broad-spectrum constitutive modeling technique applied to saline ice

The constitutive behavior of lab-grown saline ice subjected to isothermal, uniaxial tensile loadings is discussed. A rectangular plate specimen of S2 columnar saline ice was subjected to a uniform tensile stress perpendicular to the long axis of the column structure. This loading was selected to represent the stress field which occurs in the plane of natural ice covers under tension. The uniaxial stress state was applied with a recently developed, modified Reversed Direct Stress device. Two successive load histories were applied – creep-recovery cycles and monotonic stress ramps. A broad-spectrum, nonlinear viscoelastic modeling approach is used to develop a constitutive model of the strain response. Each parameter of the model is evaluated from the measured ice response to the creep-recovery loadings. The model provides an accurate representation of the experimental data with a delayed elastic compliance function in time power law form (t _n ,n= ) and a nonlinear stress exponent (σ _q ,q = ). Finally, the model is used to predict the strain response of the ice to the monotonic ramp loadings with good results. This revised version was published online in July 2006 with corrections to the Cover Date.     

Fracture analysis of semi-circular and semi-circular-bend geometries

A fracture mechanics analysis of the semi-circular (SC) and semi-circular-bend (SCB) fracture geometries is presented. The weight function method is implemented to obtain wide ranging stress intensity factor (SIF) and crack opening displacement (COD) expressions. This study has as its basis a finite element analysis of the semi-circular disk (SC) subjected to a reference loading case. The latter is required to determine both the associated reference stress intensity factor and the weight function for the base-edge-cracked semi-circular geometry. With this information, SIF and COD expressions for the full range of crack lengths are obtained. The special cases of the SC subject to a concentrated crack mouth loading and the SCB are analyzed in detail. The weight function for the SCB is fully developed, with an accurate expression for the SIF and and a numerical result for the crack mouth opening displacement (CMOD). The latter wide ranging expressions can, in turn, be applied as a reference solution. From this weight function approach, SIF's and COD's for the SC and SCB subject to any other loading can be obtained.     

The effects of nitrogen additions to a cobalt-chromium surgical implant alloy

The determination of the feasibility of adding nitrogen to a cobalt-chromium implant alloy was undertaken with the ultimate goal of the work being the improvement of the static and fatigue properties of the alloy. Nitrogen additions were made using high-temperature heat treatments in a nitrogen-containing gas atmosphere. The effects of the nitrogen additions were characterized in this study using several techniques. The maximum solid solubility of nitrogen in the alloy at 1200° C (the heat-treatment temperature) was found to be approximately 0.35 wt % N. X-ray diffraction using nitrogen heat-treated powder samples indicated that the addition of nitrogen in solution resulted in a lattice dilation lying in the range of 0.0021 to 0.0035 nm per wt % N. Above the solubility limit, Cr₂N and Cr₂(CN) were present at the nitrogen heat-treatment temperatures in the form of large second-phase particles. Ageing of the alloy containing approximately 0.35 wt % N at 400° C resulted in the precipitation of CrN. A study of the nitrogen distribution suggested that the diffusion of nitrogen ms affected by the carbon content of the cobalt-base alloy.